TY - JOUR T1 - Evidence-based mixture containing Lactobacillus strains and lactoferrin to prevent recurrent bacterial vaginosis: a double blind, placebo controlled, randomised clinical trial. JF - Benef Microbes Y1 - 2019 A1 - Russo, R A1 - Karadja, E A1 - De Seta, F AB -

Bacterial vaginosis (BV) is the most common cause of vaginal discomfort in women. It is characterised by abnormal vaginal microbiota with a depletion of lactobacilli and predominance of anaerobic microorganisms, mainly Gardnerella vaginalis and Atopobium vaginae. Although antibiotics represent an effective therapeutic option in the short-term, recurrent infections still remain a serious problem. Nowadays, evidence exists about the efficacy of probiotics for the management of BV. The aim of the current double blind, randomised clinical trial was to assess the efficacy of a probiotic mixture, including Lactobacillus acidophilus GLA-14 and Lactobacillus rhamnosus HN001, in combination with bovine lactoferrin, as adjuvant therapy to metronidazole in women with recurrent BV. In particular, normalisation of Nugent score, remission of symptoms and recurrences during a six-months follow-up were assessed. 48 adult women received metronidazole (500 mg twice daily) for 7 days and randomly assigned to take simultaneously either probiotics plus lactoferrin or placebo (2 capsules/day for 5 days followed by 1 capsule/day for 10 consecutive days; induction phase). The verum or placebo administration (1 capsule/day for 10 consecutive days) was repeated each month (maintenance phase) during the six months of follow-up starting the first day of menstrual cycle since the menstrual blood increases the vaginal pH and contributes to increase the risk of recurrences. The results showed that symptoms (vaginal discharge and itching), Nugent score and recurrence rate were significantly improved by probiotics mixture in association with lactoferrin. This alternative approach may represent a safe and effective remedy for the restoration of healthy vaginal microbiota in preventing recurrent BV.

VL - 10 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30525953?dopt=Abstract ER - TY - JOUR T1 - Loss-of-function mutations in cause a new form of inherited thrombocytopenia. JF - Blood Y1 - 2019 A1 - Marconi, Caterina A1 - Di Buduo, Christian A A1 - LeVine, Kellie A1 - Barozzi, Serena A1 - Faleschini, Michela A1 - Bozzi, Valeria A1 - Palombo, Flavia A1 - McKinstry, Spencer A1 - Lassandro, Giuseppe A1 - Giordano, Paola A1 - Noris, Patrizia A1 - Balduini, Carlo L A1 - Savoia, Anna A1 - Balduini, Alessandra A1 - Pippucci, Tommaso A1 - Seri, Marco A1 - Katsanis, Nicholas A1 - Pecci, Alessandro AB -

Inherited thrombocytopenias (ITs) are a heterogeneous group of disorders characterized by low platelet count that may result in bleeding tendency. Despite progress being made in defining the genetic causes of ITs, nearly 50% of patients with familial thrombocytopenia are affected with forms of unknown origin. Here, through exome sequencing of 2 siblings with autosomal-recessive thrombocytopenia, we identified biallelic loss-of-function variants in This gene encodes for a receptor-like PTP, PTPRJ (or CD148), which is expressed abundantly in platelets and megakaryocytes. Consistent with the predicted effects of the variants, both probands have an almost complete loss of PTPRJ at the messenger RNA and protein levels. To investigate the pathogenic role of PTPRJ deficiency in hematopoiesis in vivo, we carried out CRISPR/Cas9-mediated ablation of (the ortholog of human ) in zebrafish, which induced a significantly decreased number of CD41 thrombocytes in vivo. Moreover, megakaryocytes of our patients showed impaired maturation and profound defects in SDF1-driven migration and formation of proplatelets in vitro. Silencing of in a human megakaryocytic cell line reproduced the functional defects observed in patients' megakaryocytes. The disorder caused by mutations presented as a nonsyndromic thrombocytopenia characterized by spontaneous bleeding, small-sized platelets, and impaired platelet responses to the GPVI agonists collagen and convulxin. These platelet functional defects could be attributed to reduced activation of Src family kinases. Taken together, our data identify a new form of IT and highlight a hitherto unknown fundamental role for PTPRJ in platelet biogenesis.

VL - 133 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30591527?dopt=Abstract ER - TY - JOUR T1 - Next-generation sequencing identified SPATC1L as a possible candidate gene for both early-onset and age-related hearing loss. JF - Eur J Hum Genet Y1 - 2019 A1 - Morgan, Anna A1 - Vuckovic, Dragana A1 - Krishnamoorthy, Navaneethakrishnan A1 - Rubinato, Elisa A1 - Ambrosetti, Umberto A1 - Castorina, Pierangela A1 - Franzè, Annamaria A1 - Vozzi, Diego A1 - La Bianca, Martina A1 - Cappellani, Stefania A1 - Di Stazio, Mariateresa A1 - Gasparini, Paolo A1 - Girotto, Giorgia AB -

Hereditary hearing loss (HHL) and age-related hearing loss (ARHL) are two major sensory diseases affecting millions of people worldwide. Despite many efforts, additional HHL-genes and ARHL genetic risk factors still need to be identified. To fill this gap a large genomic screening based on next-generation sequencing technologies was performed. Whole exome sequencing in a 3-generation Italian HHL family and targeted re-sequencing in 464 ARHL patients were performed. We detected three variants in SPATC1L: a nonsense allele in an HHL family and a frameshift insertion and a missense variation in two unrelated ARHL patients. In silico molecular modelling of all variants suggested a significant impact on the structural stability of the protein itself, likely leading to deleterious effects and resulting in truncated isoforms. After demonstrating Spatc1l expression in mice inner ear, in vitro functional experiments were performed confirming the results of the molecular modelling studies. Finally, a candidate-gene population-based statistical study in cohorts from Caucasus and Central Asia revealed a statistically significant association of SPATC1L with normal hearing function at low and medium hearing frequencies. Overall, the amount of different genetic data presented here (variants with early-onset and late-onset hearing loss in addition to genetic association with normal hearing function), together with relevant functional evidence, likely suggest a role of SPATC1L in hearing function and loss.

VL - 27 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30177775?dopt=Abstract ER - TY - JOUR T1 - De novo unbalanced translocations have a complex history/aetiology. JF - Hum Genet Y1 - 2018 A1 - Bonaglia, Maria Clara A1 - Kurtas, Nehir Edibe A1 - Errichiello, Edoardo A1 - Bertuzzo, Sara A1 - Beri, Silvana A1 - Mehrjouy, Mana M A1 - Provenzano, Aldesia A1 - Vergani, Debora A1 - Pecile, Vanna A1 - Novara, Francesca A1 - Reho, Paolo A1 - Di Giacomo, Marilena Carmela A1 - Discepoli, Giancarlo A1 - Giorda, Roberto A1 - Aldred, Micheala A A1 - Santos-Rebouças, Cíntia Barros A1 - Goncalves, Andressa Pereira A1 - Abuelo, Diane N A1 - Giglio, Sabrina A1 - Ricca, Ivana A1 - Franchi, Fabrizia A1 - Patsalis, Philippos A1 - Sismani, Carolina A1 - Morí, María Angeles A1 - Nevado, Julián A1 - Tommerup, Niels A1 - Zuffardi, Orsetta KW - DNA End-Joining Repair KW - Female KW - Humans KW - Male KW - Meiosis KW - Recombinational DNA Repair KW - Translocation, Genetic AB -

We investigated 52 cases of de novo unbalanced translocations, consisting in a terminally deleted or inverted-duplicated deleted (inv-dup del) 46th chromosome to which the distal portion of another chromosome or its opposite end was transposed. Array CGH, whole-genome sequencing, qPCR, FISH, and trio genotyping were applied. A biparental origin of the deletion and duplication was detected in 6 cases, whereas in 46, both imbalances have the same parental origin. Moreover, the duplicated region was of maternal origin in more than half of the cases, with 25% of them showing two maternal and one paternal haplotype. In all these cases, maternal age was increased. These findings indicate that the primary driver for the occurrence of the de novo unbalanced translocations is a maternal meiotic non-disjunction, followed by partial trisomy rescue of the supernumerary chromosome present in the trisomic zygote. In contrast, asymmetric breakage of a dicentric chromosome, originated either at the meiosis or postzygotically, in which the two resulting chromosomes, one being deleted and the other one inv-dup del, are repaired by telomere capture, appears at the basis of all inv-dup del translocations. Notably, this mechanism also fits with the origin of some simple translocations in which the duplicated region was of paternal origin. In all cases, the signature at the translocation junctions was that of non-homologous end joining (NHEJ) rather than non-allelic homologous recombination (NAHR). Our data imply that there is no risk of recurrence in the following pregnancies for any of the de novo unbalanced translocations we discuss here.

VL - 137 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30276538?dopt=Abstract ER - TY - JOUR T1 - DEFB1 polymorphisms and HIV-1 mother-to-child transmission in Zambian population. JF - J Matern Fetal Neonatal Med Y1 - 2018 A1 - Zupin, Luisa A1 - Polesello, Vania A1 - Segat, Ludovica A1 - Kamada, Anselmo Jiro A1 - Kuhn, Louise A1 - Crovella, Sergio AB -

INTRODUCTION: Human Beta Defensin-1 (hBD-1) is a component of the innate immune system, the first line of defence against pathogens, already reported as involved in the susceptibility to HIV-1 infection and HIV-1 mother-to-child transmission (MTCT) in different populations. We investigated the role of DEFB1 gene (encoding for hBD-1) functional polymorphisms in the susceptibility to HIV-1 MTCT in a population from Zambia.

METHODS: Four selected polymorphisms within DEFB1 gene, three at the 5' untranslated region (UTR), namely -52G > A (rs1799946), -44C > G (rs1800972) and -20G > A (rs11362) and one in the 3'UTR, c.*87A > G (rs1800972), were genotyped in 101 HIV-1 positive mothers (26 transmitters -27% and 75 not transmitters -73%) and 331 infants born to HIV-1 infected mothers (85 HIV-1 positive -26% and 246 exposed but not infected -74%).

RESULTS: DEFB1 c.*87-A allele was more frequent among HIV- children with respect to HIV+ (with intrauterine MTCT). Concerning DEFB1 haplotypes, GCGA haplotype resulted more represented in HIV- than HIV+ infants and DEFB1 ACGG haplotype presented increased frequency in HIV- children respect to HIV+ (with intra-partum MTCT) (p = .02, p = .002 and p = .006, respectively).

CONCLUSIONS: DEFB1 polymorphisms were significantly associated with decreased risk of HIV-1 infection acquisition in the studied Zambian population suggesting that they may play a role in HIV-1 MTCT.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/29506422?dopt=Abstract ER - TY - JOUR T1 - Efficacy and Safety of Adalimumab in Pediatric Ulcerative Colitis: A Real-life Experience from the SIGENP-IBD Registry. JF - J Pediatr Gastroenterol Nutr Y1 - 2018 A1 - Aloi, Marina A1 - Bramuzzo, Matteo A1 - Arrigo, Serena A1 - Romano, Claudio A1 - D'Arcangelo, Giulia A1 - Lacorte, Doriana A1 - Gatti, Simona A1 - Illiceto, Maria T A1 - Zucconi, Francesca A1 - Dilillo, Dario A1 - Zuin, Giovanna A1 - Knafelz, Daniela A1 - Ravelli, Alberto A1 - Cucchiara, Salvatore A1 - Alvisi, Patrizia AB -

OBJECTIVES: The aim of this study was to evaluate the effectiveness and safety of adalimumab (ADA) in children with ulcerative colitis (UC) previously treated with infliximab (IFX).

METHODS: Retrospective study including children with UC from a national registry who received ADA therapy. The primary endpoint was the rate of corticosteroid-free remission at week 52. Secondary outcomes were the rate of sustained clinical remission, primary nonresponse, and loss of response at weeks 12, 30, and 52 and rate of mucosal healing and side effects at week 52.

RESULTS: Thirty-two children received ADA (median age 10 ± 4 years). Median disease duration before ADA therapy was 27 months. All patients received previous IFX (43% intolerant, 50% nonresponders [37.5% primary, 42.5% secondary nonresponders], 6.7% positive anti-IFX antibodies). Fifty-two weeks after ADA initiation, 13 patients (41%) were in corticosteroid-free remission. Mucosal healing occurred in 9 patients (28%) at 52 weeks. The cumulative probability of a clinical relapse-free course was 69%, 59%, and 53% at 12, 30, and 52 weeks, respectively. Ten patients (31%) had a primary failure and 5 (15%) a loss of response to ADA. No significant differences in efficacy were reported between not-responders and intolerant to IFX (P = 1.0). Overall, 19 patient (59%) maintained ADA during 52-week follow-up. Seven patients (22%) experienced an adverse event, no serious side effects were observed and none resulted in ADA discontinuation.

CONCLUSIONS: Based on our data, ADA seems to be effective in children with UC, allowing to recover a significant percentage of patients intolerant or not-responding to IFX. The safety profile was good.

VL - 66 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29315163?dopt=Abstract ER - TY - JOUR T1 - Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6. JF - Genome Biol Y1 - 2018 A1 - Prins, Bram P A1 - Mead, Timothy J A1 - Brody, Jennifer A A1 - Sveinbjornsson, Gardar A1 - Ntalla, Ioanna A1 - Bihlmeyer, Nathan A A1 - van den Berg, Marten A1 - Bork-Jensen, Jette A1 - Cappellani, Stefania A1 - Van Duijvenboden, Stefan A1 - Klena, Nikolai T A1 - Gabriel, George C A1 - Liu, Xiaoqin A1 - Gulec, Cagri A1 - Grarup, Niels A1 - Haessler, Jeffrey A1 - Hall, Leanne M A1 - Iorio, Annamaria A1 - Isaacs, Aaron A1 - Li-Gao, Ruifang A1 - Lin, Honghuang A1 - Liu, Ching-Ti A1 - Lyytikäinen, Leo-Pekka A1 - Marten, Jonathan A1 - Mei, Hao A1 - Müller-Nurasyid, Martina A1 - Orini, Michele A1 - Padmanabhan, Sandosh A1 - Radmanesh, Farid A1 - Ramirez, Julia A1 - Robino, Antonietta A1 - Schwartz, Molly A1 - van Setten, Jessica A1 - Smith, Albert V A1 - Verweij, Niek A1 - Warren, Helen R A1 - Weiss, Stefan A1 - Alonso, Alvaro A1 - Arnar, David O A1 - Bots, Michiel L A1 - de Boer, Rudolf A A1 - Dominiczak, Anna F A1 - Eijgelsheim, Mark A1 - Ellinor, Patrick T A1 - Guo, Xiuqing A1 - Felix, Stephan B A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Heckbert, Susan R A1 - Huang, Paul L A1 - Jukema, J W A1 - Kähönen, Mika A1 - Kors, Jan A A1 - Lambiase, Pier D A1 - Launer, Lenore J A1 - Li, Man A1 - Linneberg, Allan A1 - Nelson, Christopher P A1 - Pedersen, Oluf A1 - Perez, Marco A1 - Peters, Annette A1 - Polasek, Ozren A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Rice, Kenneth M A1 - Rotter, Jerome I A1 - Sinner, Moritz F A1 - Soliman, Elsayed Z A1 - Spector, Tim D A1 - Strauch, Konstantin A1 - Thorsteinsdottir, Unnur A1 - Tinker, Andrew A1 - Trompet, Stella A1 - Uitterlinden, André A1 - Vaartjes, Ilonca A1 - van der Meer, Peter A1 - Völker, Uwe A1 - Völzke, Henry A1 - Waldenberger, Melanie A1 - Wilson, James G A1 - Xie, Zhijun A1 - Asselbergs, Folkert W A1 - Dörr, Marcus A1 - van Duijn, Cornelia M A1 - Gasparini, Paolo A1 - Gudbjartsson, Daniel F A1 - Gudnason, Vilmundur A1 - Hansen, Torben A1 - Kääb, Stefan A1 - Kanters, Jørgen K A1 - Kooperberg, Charles A1 - Lehtimäki, Terho A1 - Lin, Henry J A1 - Lubitz, Steven A A1 - Mook-Kanamori, Dennis O A1 - Conti, Francesco J A1 - Newton-Cheh, Christopher H A1 - Rosand, Jonathan A1 - Rudan, Igor A1 - Samani, Nilesh J A1 - Sinagra, Gianfranco A1 - Smith, Blair H A1 - Holm, Hilma A1 - Stricker, Bruno H A1 - Ulivi, Sheila A1 - Sotoodehnia, Nona A1 - Apte, Suneel S A1 - van der Harst, Pim A1 - Stefansson, Kari A1 - Munroe, Patricia B A1 - Arking, Dan E A1 - Lo, Cecilia W A1 - Jamshidi, Yalda KW - ADAMTS Proteins KW - African Continental Ancestry Group KW - Animals KW - Connexin 43 KW - Electrocardiography KW - European Continental Ancestry Group KW - Exome KW - Female KW - Gene Expression KW - Gene Expression Profiling KW - Genetic Loci KW - Genome-Wide Association Study KW - Heart Conduction System KW - Humans KW - Male KW - Mice KW - Middle Aged KW - Myocardium KW - Open Reading Frames KW - Polymorphism, Single Nucleotide KW - Whole Exome Sequencing AB -

BACKGROUND: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear.

RESULTS: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction.

CONCLUSIONS: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.

VL - 19 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30012220?dopt=Abstract ER - TY - JOUR T1 - Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals. JF - Nat Genet Y1 - 2018 A1 - Lee, James J A1 - Wedow, Robbee A1 - Okbay, Aysu A1 - Kong, Edward A1 - Maghzian, Omeed A1 - Zacher, Meghan A1 - Nguyen-Viet, Tuan Anh A1 - Bowers, Peter A1 - Sidorenko, Julia A1 - Karlsson Linnér, Richard A1 - Fontana, Mark Alan A1 - Kundu, Tushar A1 - Lee, Chanwook A1 - Li, Hui A1 - Li, Ruoxi A1 - Royer, Rebecca A1 - Timshel, Pascal N A1 - Walters, Raymond K A1 - Willoughby, Emily A A1 - Yengo, Loic A1 - Alver, Maris A1 - Bao, Yanchun A1 - Clark, David W A1 - Day, Felix R A1 - Furlotte, Nicholas A A1 - Joshi, Peter K A1 - Kemper, Kathryn E A1 - Kleinman, Aaron A1 - Langenberg, Claudia A1 - Mägi, Reedik A1 - Trampush, Joey W A1 - Verma, Shefali Setia A1 - Wu, Yang A1 - Lam, Max A1 - Zhao, Jing Hua A1 - Zheng, Zhili A1 - Boardman, Jason D A1 - Campbell, Harry A1 - Freese, Jeremy A1 - Harris, Kathleen Mullan A1 - Hayward, Caroline A1 - Herd, Pamela A1 - Kumari, Meena A1 - Lencz, Todd A1 - Luan, Jian'an A1 - Malhotra, Anil K A1 - Metspalu, Andres A1 - Milani, Lili A1 - Ong, Ken K A1 - Perry, John R B A1 - Porteous, David J A1 - Ritchie, Marylyn D A1 - Smart, Melissa C A1 - Smith, Blair H A1 - Tung, Joyce Y A1 - Wareham, Nicholas J A1 - Wilson, James F A1 - Beauchamp, Jonathan P A1 - Conley, Dalton C A1 - Esko, Tõnu A1 - Lehrer, Steven F A1 - Magnusson, Patrik K E A1 - Oskarsson, Sven A1 - Pers, Tune H A1 - Robinson, Matthew R A1 - Thom, Kevin A1 - Watson, Chelsea A1 - Chabris, Christopher F A1 - Meyer, Michelle N A1 - Laibson, David I A1 - Yang, Jian A1 - Johannesson, Magnus A1 - Koellinger, Philipp D A1 - Turley, Patrick A1 - Visscher, Peter M A1 - Benjamin, Daniel J A1 - Cesarini, David AB -

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

VL - 50 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30038396?dopt=Abstract ER - TY - JOUR T1 - Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. JF - Nat Genet Y1 - 2018 A1 - Evangelou, Evangelos A1 - Warren, Helen R A1 - Mosen-Ansorena, David A1 - Mifsud, Borbala A1 - Pazoki, Raha A1 - Gao, He A1 - Ntritsos, Georgios A1 - Dimou, Niki A1 - Cabrera, Claudia P A1 - Karaman, Ibrahim A1 - Ng, Fu Liang A1 - Evangelou, Marina A1 - Witkowska, Katarzyna A1 - Tzanis, Evan A1 - Hellwege, Jacklyn N A1 - Giri, Ayush A1 - Velez Edwards, Digna R A1 - Sun, Yan V A1 - Cho, Kelly A1 - Gaziano, J Michael A1 - Wilson, Peter W F A1 - Tsao, Philip S A1 - Kovesdy, Csaba P A1 - Esko, Tõnu A1 - Mägi, Reedik A1 - Milani, Lili A1 - Almgren, Peter A1 - Boutin, Thibaud A1 - Debette, Stéphanie A1 - Ding, Jun A1 - Giulianini, Franco A1 - Holliday, Elizabeth G A1 - Jackson, Anne U A1 - Li-Gao, Ruifang A1 - Lin, Wei-Yu A1 - Luan, Jian'an A1 - Mangino, Massimo A1 - Oldmeadow, Christopher A1 - Prins, Bram Peter A1 - Qian, Yong A1 - Sargurupremraj, Muralidharan A1 - Shah, Nabi A1 - Surendran, Praveen A1 - Thériault, Sébastien A1 - Verweij, Niek A1 - Willems, Sara M A1 - Zhao, Jing-Hua A1 - Amouyel, Philippe A1 - Connell, John A1 - de Mutsert, Renée A1 - Doney, Alex S F A1 - Farrall, Martin A1 - Menni, Cristina A1 - Morris, Andrew D A1 - Noordam, Raymond A1 - Paré, Guillaume A1 - Poulter, Neil R A1 - Shields, Denis C A1 - Stanton, Alice A1 - Thom, Simon A1 - Abecasis, Goncalo A1 - Amin, Najaf A1 - Arking, Dan E A1 - Ayers, Kristin L A1 - Barbieri, Caterina M A1 - Batini, Chiara A1 - Bis, Joshua C A1 - Blake, Tineka A1 - Bochud, Murielle A1 - Boehnke, Michael A1 - Boerwinkle, Eric A1 - Boomsma, Dorret I A1 - Bottinger, Erwin P A1 - Braund, Peter S A1 - Brumat, Marco A1 - Campbell, Archie A1 - Campbell, Harry A1 - Chakravarti, Aravinda A1 - Chambers, John C A1 - Chauhan, Ganesh A1 - Ciullo, Marina A1 - Cocca, Massimiliano A1 - Collins, Francis A1 - Cordell, Heather J A1 - Davies, Gail A1 - de Borst, Martin H A1 - de Geus, Eco J A1 - Deary, Ian J A1 - Deelen, Joris A1 - del Greco M, Fabiola A1 - Demirkale, Cumhur Yusuf A1 - Dörr, Marcus A1 - Ehret, Georg B A1 - Elosua, Roberto A1 - Enroth, Stefan A1 - Erzurumluoglu, A Mesut A1 - Ferreira, Teresa A1 - Frånberg, Mattias A1 - Franco, Oscar H A1 - Gandin, Ilaria A1 - Gasparini, Paolo A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Girotto, Giorgia A1 - Goel, Anuj A1 - Gow, Alan J A1 - Gudnason, Vilmundur A1 - Guo, Xiuqing A1 - Gyllensten, Ulf A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Harris, Sarah E A1 - Hartman, Catharina A A1 - Havulinna, Aki S A1 - Hicks, Andrew A A1 - Hofer, Edith A1 - Hofman, Albert A1 - Hottenga, Jouke-Jan A1 - Huffman, Jennifer E A1 - Hwang, Shih-Jen A1 - Ingelsson, Erik A1 - James, Alan A1 - Jansen, Rick A1 - Järvelin, Marjo-Riitta A1 - Joehanes, Roby A1 - Johansson, Åsa A1 - Johnson, Andrew D A1 - Joshi, Peter K A1 - Jousilahti, Pekka A1 - Jukema, J Wouter A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kathiresan, Sekar A1 - Keavney, Bernard D A1 - Khaw, Kay-Tee A1 - Knekt, Paul A1 - Knight, Joanne A1 - Kolcic, Ivana A1 - Kooner, Jaspal S A1 - Koskinen, Seppo A1 - Kristiansson, Kati A1 - Kutalik, Zoltán A1 - Laan, Maris A1 - Larson, Marty A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lehtimäki, Terho A1 - Liewald, David C M A1 - Lin, Li A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Lopez, Lorna M A1 - Lu, Yingchang A1 - Lyytikäinen, Leo-Pekka A1 - Mahajan, Anubha A1 - Mamasoula, Chrysovalanto A1 - Marrugat, Jaume A1 - Marten, Jonathan A1 - Milaneschi, Yuri A1 - Morgan, Anna A1 - Morris, Andrew P A1 - Morrison, Alanna C A1 - Munson, Peter J A1 - Nalls, Mike A A1 - Nandakumar, Priyanka A1 - Nelson, Christopher P A1 - Niiranen, Teemu A1 - Nolte, Ilja M A1 - Nutile, Teresa A1 - Oldehinkel, Albertine J A1 - Oostra, Ben A A1 - O'Reilly, Paul F A1 - Org, Elin A1 - Padmanabhan, Sandosh A1 - Palmas, Walter A1 - Palotie, Aarno A1 - Pattie, Alison A1 - Penninx, Brenda W J H A1 - Perola, Markus A1 - Peters, Annette A1 - Polasek, Ozren A1 - Pramstaller, Peter P A1 - Nguyen, Quang Tri A1 - Raitakari, Olli T A1 - Ren, Meixia A1 - Rettig, Rainer A1 - Rice, Kenneth A1 - Ridker, Paul M A1 - Ried, Janina S A1 - Riese, Harriëtte A1 - Ripatti, Samuli A1 - Robino, Antonietta A1 - Rose, Lynda M A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Ruggiero, Daniela A1 - Saba, Yasaman A1 - Sala, Cinzia F A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Sarin, Antti-Pekka A1 - Schmidt, Reinhold A1 - Schmidt, Helena A1 - Shrine, Nick A1 - Siscovick, David A1 - Smith, Albert V A1 - Snieder, Harold A1 - Sõber, Siim A1 - Sorice, Rossella A1 - Starr, John M A1 - Stott, David J A1 - Strachan, David P A1 - Strawbridge, Rona J A1 - Sundström, Johan A1 - Swertz, Morris A A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Tobin, Martin D A1 - Tomaszewski, Maciej A1 - Toniolo, Daniela A1 - Traglia, Michela A1 - Trompet, Stella A1 - Tuomilehto, Jaakko A1 - Tzourio, Christophe A1 - Uitterlinden, André G A1 - Vaez, Ahmad A1 - van der Most, Peter J A1 - van Duijn, Cornelia M A1 - Vergnaud, Anne-Claire A1 - Verwoert, Germaine C A1 - Vitart, Veronique A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Vuckovic, Dragana A1 - Watkins, Hugh A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Wright, Alan F A1 - Yao, Jie A1 - Zemunik, Tatijana A1 - Zhang, Weihua A1 - Attia, John R A1 - Butterworth, Adam S A1 - Chasman, Daniel I A1 - Conen, David A1 - Cucca, Francesco A1 - Danesh, John A1 - Hayward, Caroline A1 - Howson, Joanna M M A1 - Laakso, Markku A1 - Lakatta, Edward G A1 - Langenberg, Claudia A1 - Melander, Olle A1 - Mook-Kanamori, Dennis O A1 - Palmer, Colin N A A1 - Risch, Lorenz A1 - Scott, Robert A A1 - Scott, Rodney J A1 - Sever, Peter A1 - Spector, Tim D A1 - van der Harst, Pim A1 - Wareham, Nicholas J A1 - Zeggini, Eleftheria A1 - Levy, Daniel A1 - Munroe, Patricia B A1 - Newton-Cheh, Christopher A1 - Brown, Morris J A1 - Metspalu, Andres A1 - Hung, Adriana M A1 - O'Donnell, Christopher J A1 - Edwards, Todd L A1 - Psaty, Bruce M A1 - Tzoulaki, Ioanna A1 - Barnes, Michael R A1 - Wain, Louise V A1 - Elliott, Paul A1 - Caulfield, Mark J AB -

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

VL - 50 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30224653?dopt=Abstract ER - TY - JOUR T1 - Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. JF - Am J Hum Genet Y1 - 2018 A1 - Ligthart, Symen A1 - Vaez, Ahmad A1 - Võsa, Urmo A1 - Stathopoulou, Maria G A1 - de Vries, Paul S A1 - Prins, Bram P A1 - van der Most, Peter J A1 - Tanaka, Toshiko A1 - Naderi, Elnaz A1 - Rose, Lynda M A1 - Wu, Ying A1 - Karlsson, Robert A1 - Barbalic, Maja A1 - Lin, Honghuang A1 - Pool, René A1 - Zhu, Gu A1 - Macé, Aurélien A1 - Sidore, Carlo A1 - Trompet, Stella A1 - Mangino, Massimo A1 - Sabater-Lleal, Maria A1 - Kemp, John P A1 - Abbasi, Ali A1 - Kacprowski, Tim A1 - Verweij, Niek A1 - Smith, Albert V A1 - Huang, Tao A1 - Marzi, Carola A1 - Feitosa, Mary F A1 - Lohman, Kurt K A1 - Kleber, Marcus E A1 - Milaneschi, Yuri A1 - Mueller, Christian A1 - Huq, Mahmudul A1 - Vlachopoulou, Efthymia A1 - Lyytikäinen, Leo-Pekka A1 - Oldmeadow, Christopher A1 - Deelen, Joris A1 - Perola, Markus A1 - Zhao, Jing Hua A1 - Feenstra, Bjarke A1 - Amini, Marzyeh A1 - Lahti, Jari A1 - Schraut, Katharina E A1 - Fornage, Myriam A1 - Suktitipat, Bhoom A1 - Chen, Wei-Min A1 - Li, Xiaohui A1 - Nutile, Teresa A1 - Malerba, Giovanni A1 - Luan, Jian'an A1 - Bak, Tom A1 - Schork, Nicholas A1 - del Greco M, Fabiola A1 - Thiering, Elisabeth A1 - Mahajan, Anubha A1 - Marioni, Riccardo E A1 - Mihailov, Evelin A1 - Eriksson, Joel A1 - Ozel, Ayse Bilge A1 - Zhang, Weihua A1 - Nethander, Maria A1 - Cheng, Yu-Ching A1 - Aslibekyan, Stella A1 - Ang, Wei A1 - Gandin, Ilaria A1 - Yengo, Loic A1 - Portas, Laura A1 - Kooperberg, Charles A1 - Hofer, Edith A1 - Rajan, Kumar B A1 - Schurmann, Claudia A1 - den Hollander, Wouter A1 - Ahluwalia, Tarunveer S A1 - Zhao, Jing A1 - Draisma, Harmen H M A1 - Ford, Ian A1 - Timpson, Nicholas A1 - Teumer, Alexander A1 - Huang, Hongyan A1 - Wahl, Simone A1 - Liu, Yongmei A1 - Huang, Jie A1 - Uh, Hae-Won A1 - Geller, Frank A1 - Joshi, Peter K A1 - Yanek, Lisa R A1 - Trabetti, Elisabetta A1 - Lehne, Benjamin A1 - Vozzi, Diego A1 - Verbanck, Marie A1 - Biino, Ginevra A1 - Saba, Yasaman A1 - Meulenbelt, Ingrid A1 - O'Connell, Jeff R A1 - Laakso, Markku A1 - Giulianini, Franco A1 - Magnusson, Patrik K E A1 - Ballantyne, Christie M A1 - Hottenga, Jouke Jan A1 - Montgomery, Grant W A1 - Rivadineira, Fernando A1 - Rueedi, Rico A1 - Steri, Maristella A1 - Herzig, Karl-Heinz A1 - Stott, David J A1 - Menni, Cristina A1 - Frånberg, Mattias A1 - St Pourcain, Beate A1 - Felix, Stephan B A1 - Pers, Tune H A1 - Bakker, Stephan J L A1 - Kraft, Peter A1 - Peters, Annette A1 - Vaidya, Dhananjay A1 - Delgado, Graciela A1 - Smit, Johannes H A1 - Großmann, Vera A1 - Sinisalo, Juha A1 - Seppälä, Ilkka A1 - Williams, Stephen R A1 - Holliday, Elizabeth G A1 - Moed, Matthijs A1 - Langenberg, Claudia A1 - Räikkönen, Katri A1 - Ding, Jingzhong A1 - Campbell, Harry A1 - Sale, Michele M A1 - Chen, Yii-Der I A1 - James, Alan L A1 - Ruggiero, Daniela A1 - Soranzo, Nicole A1 - Hartman, Catharina A A1 - Smith, Erin N A1 - Berenson, Gerald S A1 - Fuchsberger, Christian A1 - Hernandez, Dena A1 - Tiesler, Carla M T A1 - Giedraitis, Vilmantas A1 - Liewald, David A1 - Fischer, Krista A1 - Mellström, Dan A1 - Larsson, Anders A1 - Wang, Yunmei A1 - Scott, William R A1 - Lorentzon, Matthias A1 - Beilby, John A1 - Ryan, Kathleen A A1 - Pennell, Craig E A1 - Vuckovic, Dragana A1 - Balkau, Beverly A1 - Concas, Maria Pina A1 - Schmidt, Reinhold A1 - Mendes de Leon, Carlos F A1 - Bottinger, Erwin P A1 - Kloppenburg, Margreet A1 - Paternoster, Lavinia A1 - Boehnke, Michael A1 - Musk, A W A1 - Willemsen, Gonneke A1 - Evans, David M A1 - Madden, Pamela A F A1 - Kähönen, Mika A1 - Kutalik, Zoltán A1 - Zoledziewska, Magdalena A1 - Karhunen, Ville A1 - Kritchevsky, Stephen B A1 - Sattar, Naveed A1 - LaChance, Genevieve A1 - Clarke, Robert A1 - Harris, Tamara B A1 - Raitakari, Olli T A1 - Attia, John R A1 - van Heemst, Diana A1 - Kajantie, Eero A1 - Sorice, Rossella A1 - Gambaro, Giovanni A1 - Scott, Robert A A1 - Hicks, Andrew A A1 - Ferrucci, Luigi A1 - Standl, Marie A1 - Lindgren, Cecilia M A1 - Starr, John M A1 - Karlsson, Magnus A1 - Lind, Lars A1 - Li, Jun Z A1 - Chambers, John C A1 - Mori, Trevor A A1 - de Geus, Eco J C N A1 - Heath, Andrew C A1 - Martin, Nicholas G A1 - Auvinen, Juha A1 - Buckley, Brendan M A1 - de Craen, Anton J M A1 - Waldenberger, Melanie A1 - Strauch, Konstantin A1 - Meitinger, Thomas A1 - Scott, Rodney J A1 - McEvoy, Mark A1 - Beekman, Marian A1 - Bombieri, Cristina A1 - Ridker, Paul M A1 - Mohlke, Karen L A1 - Pedersen, Nancy L A1 - Morrison, Alanna C A1 - Boomsma, Dorret I A1 - Whitfield, John B A1 - Strachan, David P A1 - Hofman, Albert A1 - Vollenweider, Peter A1 - Cucca, Francesco A1 - Järvelin, Marjo-Riitta A1 - Jukema, J Wouter A1 - Spector, Tim D A1 - Hamsten, Anders A1 - Zeller, Tanja A1 - Uitterlinden, André G A1 - Nauck, Matthias A1 - Gudnason, Vilmundur A1 - Qi, Lu A1 - Grallert, Harald A1 - Borecki, Ingrid B A1 - Rotter, Jerome I A1 - März, Winfried A1 - Wild, Philipp S A1 - Lokki, Marja-Liisa A1 - Boyle, Michael A1 - Salomaa, Veikko A1 - Melbye, Mads A1 - Eriksson, Johan G A1 - Wilson, James F A1 - Penninx, Brenda W J H A1 - Becker, Diane M A1 - Worrall, Bradford B A1 - Gibson, Greg A1 - Krauss, Ronald M A1 - Ciullo, Marina A1 - Zaza, Gianluigi A1 - Wareham, Nicholas J A1 - Oldehinkel, Albertine J A1 - Palmer, Lyle J A1 - Murray, Sarah S A1 - Pramstaller, Peter P A1 - Bandinelli, Stefania A1 - Heinrich, Joachim A1 - Ingelsson, Erik A1 - Deary, Ian J A1 - Mägi, Reedik A1 - Vandenput, Liesbeth A1 - van der Harst, Pim A1 - Desch, Karl C A1 - Kooner, Jaspal S A1 - Ohlsson, Claes A1 - Hayward, Caroline A1 - Lehtimäki, Terho A1 - Shuldiner, Alan R A1 - Arnett, Donna K A1 - Beilin, Lawrence J A1 - Robino, Antonietta A1 - Froguel, Philippe A1 - Pirastu, Mario A1 - Jess, Tine A1 - Koenig, Wolfgang A1 - Loos, Ruth J F A1 - Evans, Denis A A1 - Schmidt, Helena A1 - Smith, George Davey A1 - Slagboom, P Eline A1 - Eiriksdottir, Gudny A1 - Morris, Andrew P A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Nolte, Ilja M A1 - Boerwinkle, Eric A1 - Visvikis-Siest, Sophie A1 - Reiner, Alex P A1 - Gross, Myron A1 - Bis, Joshua C A1 - Franke, Lude A1 - Franco, Oscar H A1 - Benjamin, Emelia J A1 - Chasman, Daniel I A1 - Dupuis, Josée A1 - Snieder, Harold A1 - Dehghan, Abbas A1 - Alizadeh, Behrooz Z AB -

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

VL - 103 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30388399?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error. JF - Nat Genet Y1 - 2018 A1 - Tedja, Milly S A1 - Wojciechowski, Robert A1 - Hysi, Pirro G A1 - Eriksson, Nicholas A1 - Furlotte, Nicholas A A1 - Verhoeven, Virginie J M A1 - Iglesias, Adriana I A1 - Meester-Smoor, Magda A A1 - Tompson, Stuart W A1 - Fan, Qiao A1 - Khawaja, Anthony P A1 - Cheng, Ching-Yu A1 - Höhn, René A1 - Yamashiro, Kenji A1 - Wenocur, Adam A1 - Grazal, Clare A1 - Haller, Toomas A1 - Metspalu, Andres A1 - Wedenoja, Juho A1 - Jonas, Jost B A1 - Wang, Ya Xing A1 - Xie, Jing A1 - Mitchell, Paul A1 - Foster, Paul J A1 - Klein, Barbara E K A1 - Klein, Ronald A1 - Paterson, Andrew D A1 - Hosseini, S Mohsen A1 - Shah, Rupal L A1 - Williams, Cathy A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Gupta, Preeti A1 - Zhao, Wanting A1 - Shi, Yuan A1 - Saw, Woei-Yuh A1 - Tai, E-Shyong A1 - Sim, Xue Ling A1 - Huffman, Jennifer E A1 - Polasek, Ozren A1 - Hayward, Caroline A1 - Bencic, Goran A1 - Rudan, Igor A1 - Wilson, James F A1 - Joshi, Peter K A1 - Tsujikawa, Akitaka A1 - Matsuda, Fumihiko A1 - Whisenhunt, Kristina N A1 - Zeller, Tanja A1 - van der Spek, Peter J A1 - Haak, Roxanna A1 - Meijers-Heijboer, Hanne A1 - van Leeuwen, Elisabeth M A1 - Iyengar, Sudha K A1 - Lass, Jonathan H A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Vingerling, Johannes R A1 - Lehtimäki, Terho A1 - Raitakari, Olli T A1 - Biino, Ginevra A1 - Concas, Maria Pina A1 - Schwantes-An, Tae-Hwi A1 - Igo, Robert P A1 - Cuellar-Partida, Gabriel A1 - Martin, Nicholas G A1 - Craig, Jamie E A1 - Gharahkhani, Puya A1 - Williams, Katie M A1 - Nag, Abhishek A1 - Rahi, Jugnoo S A1 - Cumberland, Phillippa M A1 - Delcourt, Cécile A1 - Bellenguez, Céline A1 - Ried, Janina S A1 - Bergen, Arthur A A1 - Meitinger, Thomas A1 - Gieger, Christian A1 - Wong, Tien Yin A1 - Hewitt, Alex W A1 - Mackey, David A A1 - Simpson, Claire L A1 - Pfeiffer, Norbert A1 - Pärssinen, Olavi A1 - Baird, Paul N A1 - Vitart, Veronique A1 - Amin, Najaf A1 - van Duijn, Cornelia M A1 - Bailey-Wilson, Joan E A1 - Young, Terri L A1 - Saw, Seang-Mei A1 - Stambolian, Dwight A1 - MacGregor, Stuart A1 - Guggenheim, Jeremy A A1 - Tung, Joyce Y A1 - Hammond, Christopher J A1 - Klaver, Caroline C W AB -

Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers.

VL - 50 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29808027?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability. JF - Nat Genet Y1 - 2018 A1 - Hysi, Pirro G A1 - Valdes, Ana M A1 - Liu, Fan A1 - Furlotte, Nicholas A A1 - Evans, David M A1 - Bataille, Veronique A1 - Visconti, Alessia A1 - Hemani, Gibran A1 - McMahon, George A1 - Ring, Susan M A1 - Smith, George Davey A1 - Duffy, David L A1 - Zhu, Gu A1 - Gordon, Scott D A1 - Medland, Sarah E A1 - Lin, Bochao D A1 - Willemsen, Gonneke A1 - Jan Hottenga, Jouke A1 - Vuckovic, Dragana A1 - Girotto, Giorgia A1 - Gandin, Ilaria A1 - Sala, Cinzia A1 - Concas, Maria Pina A1 - Brumat, Marco A1 - Gasparini, Paolo A1 - Toniolo, Daniela A1 - Cocca, Massimiliano A1 - Robino, Antonietta A1 - Yazar, Seyhan A1 - Hewitt, Alex W A1 - Chen, Yan A1 - Zeng, Changqing A1 - Uitterlinden, André G A1 - Ikram, M Arfan A1 - Hamer, Merel A A1 - van Duijn, Cornelia M A1 - Nijsten, Tamar A1 - Mackey, David A A1 - Falchi, Mario A1 - Boomsma, Dorret I A1 - Martin, Nicholas G A1 - Hinds, David A A1 - Kayser, Manfred A1 - Spector, Timothy D AB -

Hair color is one of the most recognizable visual traits in European populations and is under strong genetic control. Here we report the results of a genome-wide association study meta-analysis of almost 300,000 participants of European descent. We identified 123 autosomal and one X-chromosome loci significantly associated with hair color; all but 13 are novel. Collectively, single-nucleotide polymorphisms associated with hair color within these loci explain 34.6% of red hair, 24.8% of blond hair, and 26.1% of black hair heritability in the study populations. These results confirm the polygenic nature of complex phenotypes and improve our understanding of melanin pigment metabolism in humans.

VL - 50 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29662168?dopt=Abstract ER - TY - JOUR T1 - A genome-wide association study of corneal astigmatism: The CREAM Consortium. JF - Mol Vis Y1 - 2018 A1 - Shah, Rupal L A1 - Li, Qing A1 - Zhao, Wanting A1 - Tedja, Milly S A1 - Tideman, J Willem L A1 - Khawaja, Anthony P A1 - Fan, Qiao A1 - Yazar, Seyhan A1 - Williams, Katie M A1 - Verhoeven, Virginie J M A1 - Xie, Jing A1 - Wang, Ya Xing A1 - Hess, Moritz A1 - Nickels, Stefan A1 - Lackner, Karl J A1 - Pärssinen, Olavi A1 - Wedenoja, Juho A1 - Biino, Ginevra A1 - Concas, Maria Pina A1 - Uitterlinden, André A1 - Rivadeneira, Fernando A1 - Jaddoe, Vincent W V A1 - Hysi, Pirro G A1 - Sim, Xueling A1 - Tan, Nicholas A1 - Tham, Yih-Chung A1 - Sensaki, Sonoko A1 - Hofman, Albert A1 - Vingerling, Johannes R A1 - Jonas, Jost B A1 - Mitchell, Paul A1 - Hammond, Christopher J A1 - Höhn, René A1 - Baird, Paul N A1 - Wong, Tien-Yin A1 - Cheng, Chinfsg-Yu A1 - Teo, Yik Ying A1 - Mackey, David A A1 - Williams, Cathy A1 - Saw, Seang-Mei A1 - Klaver, Caroline C W A1 - Guggenheim, Jeremy A A1 - Bailey-Wilson, Joan E KW - Acid Phosphatase KW - Asian Continental Ancestry Group KW - Astigmatism KW - Claudins KW - Cohort Studies KW - Cornea KW - Corneal Diseases KW - European Continental Ancestry Group KW - Gene Expression KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Intracellular Signaling Peptides and Proteins KW - Odds Ratio KW - Polymorphism, Single Nucleotide KW - Receptor, Platelet-Derived Growth Factor alpha KW - Software AB -

Purpose: To identify genes and genetic markers associated with corneal astigmatism.

Methods: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression.

Results: The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha () gene: top SNP: rs7673984, odds ratio=1.12 (95% CI:1.08-1.16), p=5.55×10. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans-claudin-7 (), acid phosphatase 2, lysosomal (), and TNF alpha-induced protein 8 like 3 ().

Conclusions: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the gene, gene-based analysis identified three novel candidate genes, , , and , that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism.

VL - 24 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29422769?dopt=Abstract ER - TY - JOUR T1 - Joint Data Analysis in Nutritional Epidemiology: Identification of Observational Studies and Minimal Requirements. JF - J Nutr Y1 - 2018 A1 - Pinart, Mariona A1 - Nimptsch, Katharina A1 - Bouwman, Jildau A1 - Dragsted, Lars O A1 - Yang, Chen A1 - De Cock, Nathalie A1 - Lachat, Carl A1 - Perozzi, Giuditta A1 - Canali, Raffaella A1 - Lombardo, Rosario A1 - D'Archivio, Massimo A1 - Guillaume, Michèle A1 - Donneau, Anne-Françoise A1 - Jeran, Stephanie A1 - Linseisen, Jakob A1 - Kleiser, Christina A1 - Nöthlings, Ute A1 - Barbaresko, Janett A1 - Boeing, Heiner A1 - Stelmach-Mardas, Marta A1 - Heuer, Thorsten A1 - Laird, Eamon A1 - Walton, Janette A1 - Gasparini, Paolo A1 - Robino, Antonietta A1 - Castaño, Luis A1 - Rojo-Martínez, Gemma A1 - Merino, Jordi A1 - Masana, Luis A1 - Standl, Marie A1 - Schulz, Holger A1 - Biagi, Elena A1 - Nurk, Eha A1 - Matthys, Christophe A1 - Gobbetti, Marco A1 - de Angelis, Maria A1 - Windler, Eberhard A1 - Zyriax, Birgit-Christiane A1 - Tafforeau, Jean A1 - Pischon, Tobias KW - Adult KW - Biomarkers KW - Blood Glucose KW - Case-Control Studies KW - Child KW - Chronic Disease KW - Cohort Studies KW - Cross-Sectional Studies KW - Diet KW - Epidemiology KW - Europe KW - Genomics KW - Health Status KW - Humans KW - Inflammation KW - Insulin KW - Life Style KW - Lipoproteins KW - Longitudinal Studies KW - Metabolomics KW - Nutritional Status KW - Observational Studies as Topic KW - Statistics as Topic AB -

Background: Joint data analysis from multiple nutrition studies may improve the ability to answer complex questions regarding the role of nutritional status and diet in health and disease.

Objective: The objective was to identify nutritional observational studies from partners participating in the European Nutritional Phenotype Assessment and Data Sharing Initiative (ENPADASI) Consortium, as well as minimal requirements for joint data analysis.

Methods: A predefined template containing information on study design, exposure measurements (dietary intake, alcohol and tobacco consumption, physical activity, sedentary behavior, anthropometric measures, and sociodemographic and health status), main health-related outcomes, and laboratory measurements (traditional and omics biomarkers) was developed and circulated to those European research groups participating in the ENPADASI under the strategic research area of "diet-related chronic diseases." Information about raw data disposition and metadata sharing was requested. A set of minimal requirements was abstracted from the gathered information.

Results: Studies (12 cohort, 12 cross-sectional, and 2 case-control) were identified. Two studies recruited children only and the rest recruited adults. All studies included dietary intake data. Twenty studies collected blood samples. Data on traditional biomarkers were available for 20 studies, of which 17 measured lipoproteins, glucose, and insulin and 13 measured inflammatory biomarkers. Metabolomics, proteomics, and genomics or transcriptomics data were available in 5, 3, and 12 studies, respectively. Although the study authors were willing to share metadata, most refused, were hesitant, or had legal or ethical issues related to sharing raw data. Forty-one descriptors of minimal requirements for the study data were identified to facilitate data integration.

Conclusions: Combining study data sets will enable sufficiently powered, refined investigations to increase the knowledge and understanding of the relation between food, nutrition, and human health. Furthermore, the minimal requirements for study data may encourage more efficient secondary usage of existing data and provide sufficient information for researchers to draft future multicenter research proposals in nutrition.

VL - 148 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29490094?dopt=Abstract ER - TY - JOUR T1 - A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. JF - Am J Hum Genet Y1 - 2018 A1 - Sung, Yun J A1 - Winkler, Thomas W A1 - de Las Fuentes, Lisa A1 - Bentley, Amy R A1 - Brown, Michael R A1 - Kraja, Aldi T A1 - Schwander, Karen A1 - Ntalla, Ioanna A1 - Guo, Xiuqing A1 - Franceschini, Nora A1 - Lu, Yingchang A1 - Cheng, Ching-Yu A1 - Sim, Xueling A1 - Vojinovic, Dina A1 - Marten, Jonathan A1 - Musani, Solomon K A1 - Li, Changwei A1 - Feitosa, Mary F A1 - Kilpeläinen, Tuomas O A1 - Richard, Melissa A A1 - Noordam, Raymond A1 - Aslibekyan, Stella A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Dorajoo, Rajkumar A1 - Liu, Yongmei A1 - Manning, Alisa K A1 - Rankinen, Tuomo A1 - Smith, Albert Vernon A1 - Tajuddin, Salman M A1 - Tayo, Bamidele O A1 - Warren, Helen R A1 - Zhao, Wei A1 - Zhou, Yanhua A1 - Matoba, Nana A1 - Sofer, Tamar A1 - Alver, Maris A1 - Amini, Marzyeh A1 - Boissel, Mathilde A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Gandin, Ilaria A1 - Gao, Chuan A1 - Giulianini, Franco A1 - Goel, Anuj A1 - Harris, Sarah E A1 - Hartwig, Fernando Pires A1 - Horimoto, Andrea R V R A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Kähönen, Mika A1 - Kasturiratne, Anuradhani A1 - Kuhnel, Brigitte A1 - Leander, Karin A1 - Lee, Wen-Jane A1 - Lin, Keng-Hung A1 - 'an Luan, Jian A1 - McKenzie, Colin A A1 - Meian, He A1 - Nelson, Christopher P A1 - Rauramaa, Rainer A1 - Schupf, Nicole A1 - Scott, Robert A A1 - Sheu, Wayne H H A1 - Stančáková, Alena A1 - Takeuchi, Fumihiko A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Wang, Heming A1 - Wang, Yajuan A1 - Ware, Erin B A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Afaq, Saima A1 - Alfred, Tamuno A1 - Amin, Najaf A1 - Arking, Dan A1 - Aung, Tin A1 - Barr, R Graham A1 - Bielak, Lawrence F A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Braund, Peter S A1 - Brody, Jennifer A A1 - Broeckel, Ulrich A1 - Cabrera, Claudia P A1 - Cade, Brian A1 - Caizheng, Yu A1 - Campbell, Archie A1 - Canouil, Mickaël A1 - Chakravarti, Aravinda A1 - Chauhan, Ganesh A1 - Christensen, Kaare A1 - Cocca, Massimiliano A1 - Collins, Francis S A1 - Connell, John M A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - Debette, Stéphanie A1 - Dörr, Marcus A1 - Duan, Qing A1 - Eaton, Charles B A1 - Ehret, Georg A1 - Evangelou, Evangelos A1 - Faul, Jessica D A1 - Fisher, Virginia A A1 - Forouhi, Nita G A1 - Franco, Oscar H A1 - Friedlander, Yechiel A1 - Gao, He A1 - Gigante, Bruna A1 - Graff, Misa A1 - Gu, C Charles A1 - Gu, Dongfeng A1 - Gupta, Preeti A1 - Hagenaars, Saskia P A1 - Harris, Tamara B A1 - He, Jiang A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hirata, Makoto A1 - Hofman, Albert A1 - Howard, Barbara V A1 - Hunt, Steven A1 - Irvin, Marguerite R A1 - Jia, Yucheng A1 - Joehanes, Roby A1 - Justice, Anne E A1 - Katsuya, Tomohiro A1 - Kaufman, Joel A1 - Kerrison, Nicola D A1 - Khor, Chiea Chuen A1 - Koh, Woon-Puay A1 - Koistinen, Heikki A A1 - Komulainen, Pirjo A1 - Kooperberg, Charles A1 - Krieger, Jose E A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lewis, Cora E A1 - Li, Yize A1 - Lim, Sing Hui A1 - Lin, Shiow A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Liu, Jingmin A1 - Liu, Kiang A1 - Liu, Yeheng A1 - Loh, Marie A1 - Lohman, Kurt K A1 - Long, Jirong A1 - Louie, Tin A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milani, Lili A1 - Momozawa, Yukihide A1 - Morris, Andrew P A1 - Mosley, Thomas H A1 - Munson, Peter A1 - Murray, Alison D A1 - Nalls, Mike A A1 - Nasri, Ubaydah A1 - Norris, Jill M A1 - North, Kari A1 - Ogunniyi, Adesola A1 - Padmanabhan, Sandosh A1 - Palmas, Walter R A1 - Palmer, Nicholette D A1 - Pankow, James S A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Raitakari, Olli T A1 - Renstrom, Frida A1 - Rice, Treva K A1 - Ridker, Paul M A1 - Robino, Antonietta A1 - Robinson, Jennifer G A1 - Rose, Lynda M A1 - Rudan, Igor A1 - Sabanayagam, Charumathi A1 - Salako, Babatunde L A1 - Sandow, Kevin A1 - Schmidt, Carsten O A1 - Schreiner, Pamela J A1 - Scott, William R A1 - Seshadri, Sudha A1 - Sever, Peter A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Starr, John M A1 - Strauch, Konstantin A1 - Tang, Hua A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Uitterlinden, André G A1 - Waldenberger, Melanie A1 - Wang, Lihua A1 - Wang, Ya X A1 - Wei, Wen Bin A1 - Williams, Christine A1 - Wilson, Gregory A1 - Wojczynski, Mary K A1 - Yao, Jie A1 - Yuan, Jian-Min A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Chambers, John C A1 - Chen, Yii-Der Ida A1 - de Faire, Ulf A1 - Deary, Ian J A1 - Esko, Tõnu A1 - Farrall, Martin A1 - Forrester, Terrence A1 - Franks, Paul W A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Horta, Bernardo Lessa A1 - Hung, Yi-Jen A1 - Jonas, Jost B A1 - Kato, Norihiro A1 - Kooner, Jaspal S A1 - Laakso, Markku A1 - Lehtimäki, Terho A1 - Liang, Kae-Woei A1 - Magnusson, Patrik K E A1 - Newman, Anne B A1 - Oldehinkel, Albertine J A1 - Pereira, Alexandre C A1 - Redline, Susan A1 - Rettig, Rainer A1 - Samani, Nilesh J A1 - Scott, James A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wickremasinghe, Ananda R A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Kamatani, Yoichiro A1 - Laurie, Cathy C A1 - Bouchard, Claude A1 - Cooper, Richard S A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Kardia, Sharon L R A1 - Kritchevsky, Stephen B A1 - Levy, Daniel A1 - O'Connell, Jeff R A1 - Psaty, Bruce M A1 - van Dam, Rob M A1 - Sims, Mario A1 - Arnett, Donna K A1 - Mook-Kanamori, Dennis O A1 - Kelly, Tanika N A1 - Fox, Ervin R A1 - Hayward, Caroline A1 - Fornage, Myriam A1 - Rotimi, Charles N A1 - Province, Michael A A1 - van Duijn, Cornelia M A1 - Tai, E Shyong A1 - Wong, Tien Yin A1 - Loos, Ruth J F A1 - Reiner, Alex P A1 - Rotter, Jerome I A1 - Zhu, Xiaofeng A1 - Bierut, Laura J A1 - Gauderman, W James A1 - Caulfield, Mark J A1 - Elliott, Paul A1 - Rice, Kenneth A1 - Munroe, Patricia B A1 - Morrison, Alanna C A1 - Cupples, L Adrienne A1 - Rao, Dabeeru C A1 - Chasman, Daniel I KW - Blood Pressure KW - Cohort Studies KW - Continental Population Groups KW - Diastole KW - Epistasis, Genetic KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Reproducibility of Results KW - Smoking KW - Systole AB -

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

VL - 102 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29455858?dopt=Abstract ER - TY - JOUR T1 - Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries. JF - PLoS One Y1 - 2018 A1 - Feitosa, Mary F A1 - Kraja, Aldi T A1 - Chasman, Daniel I A1 - Sung, Yun J A1 - Winkler, Thomas W A1 - Ntalla, Ioanna A1 - Guo, Xiuqing A1 - Franceschini, Nora A1 - Cheng, Ching-Yu A1 - Sim, Xueling A1 - Vojinovic, Dina A1 - Marten, Jonathan A1 - Musani, Solomon K A1 - Li, Changwei A1 - Bentley, Amy R A1 - Brown, Michael R A1 - Schwander, Karen A1 - Richard, Melissa A A1 - Noordam, Raymond A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Dorajoo, Rajkumar A1 - Fisher, Virginia A1 - Hartwig, Fernando P A1 - Horimoto, Andrea R V R A1 - Lohman, Kurt K A1 - Manning, Alisa K A1 - Rankinen, Tuomo A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Wojczynski, Mary K A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Cai, Qiuyin A1 - Campbell, Archie A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Gao, Chuan A1 - Goel, Anuj A1 - Hagemeijer, Yanick A1 - Harris, Sarah E A1 - He, Meian A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Kähönen, Mika A1 - Kasturiratne, Anuradhani A1 - Komulainen, Pirjo A1 - Kuhnel, Brigitte A1 - Laguzzi, Federica A1 - Luan, Jian'an A1 - Matoba, Nana A1 - Nolte, Ilja M A1 - Padmanabhan, Sandosh A1 - Riaz, Muhammad A1 - Rueedi, Rico A1 - Robino, Antonietta A1 - Said, M Abdullah A1 - Scott, Robert A A1 - Sofer, Tamar A1 - Stančáková, Alena A1 - Takeuchi, Fumihiko A1 - Tayo, Bamidele O A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Vitart, Veronique A1 - Wang, Yajuan A1 - Ware, Erin B A1 - Warren, Helen R A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Afaq, Saima A1 - Amin, Najaf A1 - Amini, Marzyeh A1 - Arking, Dan E A1 - Aung, Tin A1 - Boerwinkle, Eric A1 - Borecki, Ingrid A1 - Broeckel, Ulrich A1 - Brown, Morris A1 - Brumat, Marco A1 - Burke, Gregory L A1 - Canouil, Mickaël A1 - Chakravarti, Aravinda A1 - Charumathi, Sabanayagam A1 - Ida Chen, Yii-Der A1 - Connell, John M A1 - Correa, Adolfo A1 - de Las Fuentes, Lisa A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - Deng, Xuan A1 - Ding, Jingzhong A1 - Duan, Qing A1 - Eaton, Charles B A1 - Ehret, Georg A1 - Eppinga, Ruben N A1 - Evangelou, Evangelos A1 - Faul, Jessica D A1 - Felix, Stephan B A1 - Forouhi, Nita G A1 - Forrester, Terrence A1 - Franco, Oscar H A1 - Friedlander, Yechiel A1 - Gandin, Ilaria A1 - Gao, He A1 - Ghanbari, Mohsen A1 - Gigante, Bruna A1 - Gu, C Charles A1 - Gu, Dongfeng A1 - Hagenaars, Saskia P A1 - Hallmans, Goran A1 - Harris, Tamara B A1 - He, Jiang A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hirata, Makoto A1 - Howard, Barbara V A1 - Ikram, M Arfan A1 - John, Ulrich A1 - Katsuya, Tomohiro A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Krieger, Jose E A1 - Kritchevsky, Stephen B A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Lakka, Timo A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lewis, Cora E A1 - Li, Yize A1 - Lin, Shiow A1 - Liu, Jianjun A1 - Liu, Jingmin A1 - Loh, Marie A1 - Louie, Tin A1 - Mägi, Reedik A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Milani, Lili A1 - Mohlke, Karen L A1 - Momozawa, Yukihide A1 - Nalls, Mike A A1 - Nelson, Christopher P A1 - Sotoodehnia, Nona A1 - Norris, Jill M A1 - O'Connell, Jeff R A1 - Palmer, Nicholette D A1 - Perls, Thomas A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Poulter, Neil A1 - Raffel, Leslie J A1 - Raitakari, Olli T A1 - Roll, Kathryn A1 - Rose, Lynda M A1 - Rosendaal, Frits R A1 - Rotter, Jerome I A1 - Schmidt, Carsten O A1 - Schreiner, Pamela J A1 - Schupf, Nicole A1 - Scott, William R A1 - Sever, Peter S A1 - Shi, Yuan A1 - Sidney, Stephen A1 - Sims, Mario A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Starr, John M A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Tan, Nicholas Y Q A1 - Tang, Hua A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Turner, Stephen T A1 - Uitterlinden, André G A1 - Vollenweider, Peter A1 - Waldenberger, Melanie A1 - Wang, Lihua A1 - Wang, Ya Xing A1 - Wei, Wen Bin A1 - Williams, Christine A1 - Yao, Jie A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Chambers, John C A1 - Deary, Ian J A1 - Esko, Tõnu A1 - Farrall, Martin A1 - Franks, Paul W A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Jonas, Jost Bruno A1 - Kamatani, Yoichiro A1 - Kato, Norihiro A1 - Kooner, Jaspal S A1 - Kutalik, Zoltán A1 - Laakso, Markku A1 - Laurie, Cathy C A1 - Leander, Karin A1 - Lehtimäki, Terho A1 - Study, Lifelines Cohort A1 - Magnusson, Patrik K E A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda W J H A1 - Polasek, Ozren A1 - Porteous, David J A1 - Rauramaa, Rainer A1 - Samani, Nilesh J A1 - Scott, James A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wickremasinghe, Ananda R A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Bouchard, Claude A1 - Christensen, Kaare A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Horta, Bernardo L A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Pereira, Alexandre C A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - van Dam, Rob M A1 - Gauderman, W James A1 - Zhu, Xiaofeng A1 - Mook-Kanamori, Dennis O A1 - Fornage, Myriam A1 - Rotimi, Charles N A1 - Cupples, L Adrienne A1 - Kelly, Tanika N A1 - Fox, Ervin R A1 - Hayward, Caroline A1 - van Duijn, Cornelia M A1 - Tai, E Shyong A1 - Wong, Tien Yin A1 - Kooperberg, Charles A1 - Palmas, Walter A1 - Rice, Kenneth A1 - Morrison, Alanna C A1 - Elliott, Paul A1 - Caulfield, Mark J A1 - Munroe, Patricia B A1 - Rao, Dabeeru C A1 - Province, Michael A A1 - Levy, Daniel KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Alcohol Drinking KW - Blood Pressure KW - Cohort Studies KW - Continental Population Groups KW - Female KW - Gene-Environment Interaction KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Pedigree KW - Polymorphism, Single Nucleotide KW - Young Adult AB -

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

VL - 13 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29912962?dopt=Abstract ER - TY - JOUR T1 - Nutrient intakes in an Italian population of infants during the complementary feeding period. JF - Public Health Nutr Y1 - 2018 A1 - Concina, Federica A1 - Pani, Paola A1 - Bravo, Giulia A1 - Barbone, Fabio A1 - Carletti, Claudia V A1 - Knowles, Alessandra A1 - Ronfani, Luca A1 - Parpinel, Maria AB -

OBJECTIVE: To describe the nutrient intakes of an Italian cohort of infants at 6, 9 and 12 months of age.

DESIGN: Dietary data were collected using a food diary at three follow-ups (6, 9 and 12 months of age of infants). The infants' dietary data were used to estimate nutrient intakes using the Italian food composition database integrated with data from nutritional labels and the literature. The mean and standard deviation, median and interquartile range, minimum and maximum, and 5th, 25th, 75th and 95th percentiles were calculated for the daily intake of twenty-eight nutrients, with sex differences evaluated using parametric/non-parametric statistical methods.

SETTING: A prospective population-based birth cohort.SubjectInfants (n 400) living in the urban area of Trieste (Italy).

RESULTS: The sex distribution was fairly balanced at each follow-up. The mean daily intakes of energy and the other twenty-seven nutrients considered were greater in males at all follow-ups. In particular, a significant statistical difference was observed in higher male consumption of cholesterol at 9 months and in energy and carbohydrate intakes at 12 months (P < 0·05). The mean daily intake of proteins was greater than that recommended by the Italian Dietary Reference Values at all follow-ups.

CONCLUSIONS: These preliminary results provide a useful basis for understanding the nutrient intake patterns of infants in this area of Italy during the first year of life.

VL - 21 IS - 16 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30157987?dopt=Abstract ER - TY - JOUR T1 - Pathological Significance and Prognostic Value of Surfactant Protein D in Cancer. JF - Front Immunol Y1 - 2018 A1 - Mangogna, Alessandro A1 - Belmonte, Beatrice A1 - Agostinis, Chiara A1 - Ricci, Giuseppe A1 - Gulino, Alessandro A1 - Ferrara, Ines A1 - Zanconati, Fabrizio A1 - Tripodo, Claudio A1 - Romano, Federico A1 - Kishore, Uday A1 - Bulla, Roberta AB -

Surfactant protein D (SP-D) is a pattern recognition molecule belonging to the Collectin (collagen-containing C-type lectin) family that has pulmonary as well as extra-pulmonary existence. In the lungs, it is a well-established opsonin that can agglutinate a range of microbes, and enhance their clearance phagocytosis and super-oxidative burst. It can interfere with allergen-IgE interaction and suppress basophil and mast cell activation. However, it is now becoming evident that SP-D is likely to be an innate immune surveillance molecule against tumor development. SP-D has been shown to induce apoptosis in sensitized eosinophils derived from allergic patients and a leukemic cell line p53 pathway. Recently, SP-D has been shown to suppress lung cancer progression interference with the epidermal growth factor signaling. In addition, a truncated form of recombinant human SP-D has been reported to induce apoptosis in pancreatic adenocarcinoma Fas-mediated pathway in a p53-independent manner. To further establish a correlation between SP-D presence/levels and normal and cancer tissues, we performed a bioinformatics analysis, using Oncomine dataset and the survival analysis platforms Kaplan-Meier plotter, to assess if SP-D can serve as a potential prognostic marker for human lung cancer, in addition to human gastric, breast, and ovarian cancers. We also analyzed immunohistochemically the presence of SP-D in normal and tumor human tissues. We conclude that (1) in the lung, gastric, and breast cancers, there is a lower expression of SP-D than normal tissues; (2) in ovarian cancer, there is a higher expression of SP-D than normal tissue; and (3) in lung cancer, the presence of SP-D could be associated with a favorable prognosis. On the contrary, at non-pulmonary sites such as gastric, breast, and ovarian cancers, the presence of SP-D could be associated with unfavorable prognosis. Correlation between the levels of SP-D and overall survival requires further investigation. Our analysis involves a large number of dataset; therefore, any trend observed is reliable. Despite apparent complexity within the results, it is evident that cancer tissues that produce less levels of SP-D compared to their normal tissue counterparts are probably less susceptible to SP-D-mediated immune surveillance mechanisms infiltrating immune cells.

VL - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30127783?dopt=Abstract ER - TY - JOUR T1 - Photobiomodulation at Multiple Wavelengths Differentially Modulates Oxidative Stress and . JF - Oxid Med Cell Longev Y1 - 2018 A1 - Rupel, Katia A1 - Zupin, Luisa A1 - Colliva, Andrea A1 - Kamada, Anselmo A1 - Poropat, Augusto A1 - Ottaviani, Giulia A1 - Gobbo, Margherita A1 - Fanfoni, Lidia A1 - Gratton, Rossella A1 - Santoro, Massimo A1 - Di Lenarda, Roberto A1 - Biasotto, Matteo A1 - Zacchigna, Serena KW - Adult KW - Aged KW - Aged, 80 and over KW - Female KW - Humans KW - Keratinocytes KW - Lasers, Semiconductor KW - Low-Level Light Therapy KW - Male KW - Middle Aged KW - Neutrophils KW - Oxidation-Reduction KW - Oxidative Stress KW - Stomatitis AB -

Photobiomodulation (PBM) is emerging as an effective strategy for the management of multiple inflammatory conditions, including oral mucositis (OM) in cancer patients who receive chemotherapy or radiotherapy. Still, the poor understanding of the mechanisms by which the light interacts with biological tissues and the heterogeneity of light sources and protocols employed worldwide significantly limits its applicability. Reactive oxygen species (ROS) are massively generated during the early phases of OM and play a major role in the pathogenesis of inflammation in general. Here, we report the results of a clinical and experimental study, aimed at evaluating the effect of laser light at different wavelengths on oxidative stress in oncologic patients suffering from OM and in two cell types abundantly present within the inflamed oral mucosa, neutrophil polymorphonuclear (PMN) granulocytes, and keratinocytes. In addition to standard ROS detection methods, we exploited a roGFP2-Orp1 genetically encoded sensor, allowing specific, quantitative, and dynamic imaging of redox events in living cells in response to oxidative stress and PBM. We found that the various wavelengths differentially modulate ROS production. In particular, the 660 nm laser light increases ROS production when applied either before or after an oxidative stimulus. In contrast, the 970 nm laser light exerted a moderate antioxidant activity both in the saliva of OM patients and in both cell types. The most marked reduction in the levels of ROS was detected in cells exposed either to the 800 nm laser light or to the combination of the three wavelengths. Overall, our study demonstrates that PBM exerts different effects on the redox state of both PMNs and keratinocytes depending on the used wavelength and prompts the validation of a multiwavelength protocol in the clinical settings.

VL - 2018 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30534349?dopt=Abstract ER - TY - JOUR T1 - PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity. JF - Nat Commun Y1 - 2018 A1 - van Setten, Jessica A1 - Brody, Jennifer A A1 - Jamshidi, Yalda A1 - Swenson, Brenton R A1 - Butler, Anne M A1 - Campbell, Harry A1 - Del Greco, Fabiola M A1 - Evans, Daniel S A1 - Gibson, Quince A1 - Gudbjartsson, Daniel F A1 - Kerr, Kathleen F A1 - Krijthe, Bouwe P A1 - Lyytikäinen, Leo-Pekka A1 - Müller, Christian A1 - Müller-Nurasyid, Martina A1 - Nolte, Ilja M A1 - Padmanabhan, Sandosh A1 - Ritchie, Marylyn D A1 - Robino, Antonietta A1 - Smith, Albert V A1 - Steri, Maristella A1 - Tanaka, Toshiko A1 - Teumer, Alexander A1 - Trompet, Stella A1 - Ulivi, Sheila A1 - Verweij, Niek A1 - Yin, Xiaoyan A1 - Arnar, David O A1 - Asselbergs, Folkert W A1 - Bader, Joel S A1 - Barnard, John A1 - Bis, Josh A1 - Blankenberg, Stefan A1 - Boerwinkle, Eric A1 - Bradford, Yuki A1 - Buckley, Brendan M A1 - Chung, Mina K A1 - Crawford, Dana A1 - den Hoed, Marcel A1 - Denny, Josh C A1 - Dominiczak, Anna F A1 - Ehret, Georg B A1 - Eijgelsheim, Mark A1 - Ellinor, Patrick T A1 - Felix, Stephan B A1 - Franco, Oscar H A1 - Franke, Lude A1 - Harris, Tamara B A1 - Holm, Hilma A1 - Ilaria, Gandin A1 - Iorio, Annamaria A1 - Kähönen, Mika A1 - Kolcic, Ivana A1 - Kors, Jan A A1 - Lakatta, Edward G A1 - Launer, Lenore J A1 - Lin, Honghuang A1 - Lin, Henry J A1 - Loos, Ruth J F A1 - Lubitz, Steven A A1 - Macfarlane, Peter W A1 - Magnani, Jared W A1 - Leach, Irene Mateo A1 - Meitinger, Thomas A1 - Mitchell, Braxton D A1 - Munzel, Thomas A1 - Papanicolaou, George J A1 - Peters, Annette A1 - Pfeufer, Arne A1 - Pramstaller, Peter P A1 - Raitakari, Olli T A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Samani, Nilesh J A1 - Schlessinger, David A1 - Silva Aldana, Claudia T A1 - Sinner, Moritz F A1 - Smith, Jonathan D A1 - Snieder, Harold A1 - Soliman, Elsayed Z A1 - Spector, Timothy D A1 - Stott, David J A1 - Strauch, Konstantin A1 - Tarasov, Kirill V A1 - Thorsteinsdottir, Unnur A1 - Uitterlinden, André G A1 - Van Wagoner, David R A1 - Völker, Uwe A1 - Völzke, Henry A1 - Waldenberger, Melanie A1 - Jan Westra, Harm A1 - Wild, Philipp S A1 - Zeller, Tanja A1 - Alonso, Alvaro A1 - Avery, Christy L A1 - Bandinelli, Stefania A1 - Benjamin, Emelia J A1 - Cucca, Francesco A1 - Dörr, Marcus A1 - Ferrucci, Luigi A1 - Gasparini, Paolo A1 - Gudnason, Vilmundur A1 - Hayward, Caroline A1 - Heckbert, Susan R A1 - Hicks, Andrew A A1 - Jukema, J Wouter A1 - Kääb, Stefan A1 - Lehtimäki, Terho A1 - Liu, Yongmei A1 - Munroe, Patricia B A1 - Parsa, Afshin A1 - Polasek, Ozren A1 - Psaty, Bruce M A1 - Roden, Dan M A1 - Schnabel, Renate B A1 - Sinagra, Gianfranco A1 - Stefansson, Kari A1 - Stricker, Bruno H A1 - van der Harst, Pim A1 - van Duijn, Cornelia M A1 - Wilson, James F A1 - Gharib, Sina A A1 - de Bakker, Paul I W A1 - Isaacs, Aaron A1 - Arking, Dan E A1 - Sotoodehnia, Nona KW - Atrial Function KW - Atrioventricular Node KW - Electrocardiography KW - Electrophysiological Phenomena KW - Female KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - Male KW - Mutation, Missense KW - Risk Factors AB -

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

VL - 9 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30046033?dopt=Abstract ER - TY - JOUR T1 - Repositioning of Tak-475 In Mevalonate Kinase Disease: Translating Theory Into Practice. JF - Curr Med Chem Y1 - 2018 A1 - Marcuzzi, Annalisa A1 - Loganes, Claudia A1 - Celeghini, Claudio A1 - Kleiner, Giulio KW - Acyl Coenzyme A KW - Cholesterol KW - Drug Repositioning KW - Farnesyl-Diphosphate Farnesyltransferase KW - Humans KW - Hypercholesterolemia KW - Mevalonate Kinase Deficiency KW - Oxazepines KW - Phosphotransferases (Alcohol Group Acceptor) KW - Piperidines AB -

BACKGROUND: Mevalonate Kinase Deficiency (MKD, OMIM #610377) is a rare autosomal recessive metabolic and inflammatory disease. In MKD, defective function of the enzyme mevalonate kinase, due to a mutation in the MVK gene, leads to the shortage of mevalonate- derived intermediates, which results in unbalanced prenylation of proteins and altered metabolism of sterols. These defects lead to a complex multisystem inflammatory and metabolic syndrome.

OBJECTIVE: Although biologic therapies aimed at blocking the inflammatory cytokine interleukin- 1 can significantly reduce inflammation, they cannot completely control the clinical symptoms that affect the nervous system. For this reason, MKD can still be considered an orphan drug disease. The availability of MKD models reproducing the MKD-systematic inflammation, is crucial to improve the knowledge on its pathogenesis, which is still unknown. New therapies are also required in order to improve pateints' conditions and their quality of life.

METHODS: MKD-cellular models can be obtained by biochemical inhibition of mevalonatederived isoprenoids. Of note, these cells present an exaggerated response to inflammatory stimuli that can be reduced by treatment with zaragozic acid, an inhibitor of squalene synthase, thus increasing the availability of isoprenoids intermediates upstream the enzymatic block.

RESULTS: A similar action might be obtained by lapaquistat acetate (TAK-475, Takeda), a drug that underwent extensive clinical trials as a cholesterol lowering agent 10 years ago, with a good safety profile.

CONCLUSIONS: Here we describe the preclinical evidence supporting the possible repositioning of TAK-475 from its originally intended use to the treatment of MKD and discuss its potential to modulate the mevalonate pathway in inflammatory diseases.

VL - 25 IS - 24 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28901277?dopt=Abstract ER - TY - JOUR T1 - Teaching pain recognition through art: the Ramsay-Caravaggio sedation scale. JF - Ital J Pediatr Y1 - 2018 A1 - Poropat, Federico A1 - Cozzi, Giorgio A1 - Magnolato, Andrea A1 - Monasta, Lorenzo A1 - Borrometi, Fabio A1 - Krauss, Baruch A1 - Ventura, Alessandro A1 - Barbi, Egidio KW - Clinical Competence KW - Conscious Sedation KW - Deep Sedation KW - Education, Medical, Graduate KW - Female KW - Hospitals, University KW - Humans KW - Internship and Residency KW - Italy KW - Male KW - Medicine in the Arts KW - Monitoring, Physiologic KW - Pain Measurement KW - Paintings KW - Pediatrics KW - Video Recording AB -

BACKGROUND: Clinical observation is a key component of medical ability, enabling immediate evaluation of the patient's emotional state and contributing to a clinical clue that leads to final decision making. In medical schools, the art of learning to look can be taught using medical humanities and especially visual arts. By presenting a Ramsay sedation score (RSS) integrated with Caravaggio's paintings during a procedural sedation conference for pediatric residents, we want to test the effectiveness of this approach to improve the quality of learning.

METHODS: In this preliminary study, we presented videos showing sedated pediatric patients in the setting of a procedural sedation lesson to two randomized groups of residents, one attending a lesson on RSS explained through the masterpieces of Caravaggio, the other without artistic support. A week later we tested their learning with ten multi-choice questions focused on theoretical questions about sedation monitoring and ten more questions focused on recognizing the appropriate RSS viewing the videos. The primary outcome was the comparison of the total number of RSS layers properly recognized in both groups. We also evaluated the appreciation of the residents of the use of works of art integrated with the lesson.

RESULTS: Eleven students were randomized to each group. Two residents in the standard lesson did not attend the test. The percentage of correct answers on the theoretical part was similar, 82% in the art group and 89% in the other (p > 0.05). No difference was found in the video recognition part of the RSS recognition test. Residents exposed to paintings shown great appreciation for the integration of the lesson with the Caravaggio's masterpieces.

CONCLUSIONS: Adding artwork to a standard medical conference does not improve the performance of student tests, although this approach has been greatly appreciated by residents.

VL - 44 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29386058?dopt=Abstract ER - TY - JOUR T1 - What is the quality of the maternal near-miss case reviews in WHO European Region? Cross-sectional study in Armenia, Georgia, Latvia, Republic of Moldova and Uzbekistan. JF - BMJ Open Y1 - 2018 A1 - Bacci, Alberta A1 - Hodorogea, Stelian A1 - Khachatryan, Henrik A1 - Babojonova, Shohida A1 - Irsa, Signe A1 - Jansone, Maira A1 - Dondiuc, Iurie A1 - Matarazde, George A1 - Lazdane, Gunta A1 - Lazzerini, Marzia KW - Armenia KW - Checklist KW - Cross-Sectional Studies KW - Female KW - Georgia KW - Humans KW - Latvia KW - Maternal Mortality KW - Medical Audit KW - Moldova KW - Near Miss, Healthcare KW - Pregnancy KW - Pregnancy Complications KW - Quality Improvement KW - Uzbekistan AB -

OBJECTIVES: The maternal near-miss case review (NMCR) cycle is a type of clinical audit aiming at improving quality of maternal healthcare by discussing near-miss cases. In several countries this approach has been introduced and supported by WHO and partners since 2004, but information on the quality of its implementation is missing. This study aimed at evaluating the quality of the NMCR implementation in selected countries within WHO European Region.

DESIGN: Cross-sectional study.

SETTINGS: Twenty-three maternity units in Armenia, Georgia, Latvia, Moldova and Uzbekistan.

ASSESSMENT TOOLS: A predefined checklist including 50 items, according to WHO methodology. Quality in the NMCR implementation was defined by summary scores ranging from 0 (totally inappropriate) to 3 (appropriate).

RESULTS: Quality of the NMCR implementation was heterogeneous among different countries, and within the same country. Overall, the first part of the audit cycle (from case identification to case analysis) was fairly well performed (mean score 2.00, 95% CI 1.94 to 2.06), with the exception of the 'inclusion of users' views' (mean score 0.66, 95% CI 0.11 to 1.22), while the second part (developing recommendations, implementing them and ensuring quality) was poorly performed (mean score 0.66, 95% CI 0.11 to 1.22). Each country had at least one champion facility, where quality of the NMCR cycle was acceptable. Quality of the implementation was not associated with its duration. Gaps in implementation were of technical, organisational and attitudinal nature.

CONCLUSIONS: Ensuring quality in the NMCR may be difficult but achievable. The high heterogeneity in results within the same country suggests that quality of the NMCR implementation depends, to a large extent, from hospital factors, including staff's commitment, managerial support and local coordination. Efforts should be put in preventing and mitigating common barriers that hamper successful NMCR implementation.

VL - 8 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29654004?dopt=Abstract ER - TY - JOUR T1 - 1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function. JF - Sci Rep Y1 - 2017 A1 - Gorski, Mathias A1 - van der Most, Peter J A1 - Teumer, Alexander A1 - Chu, Audrey Y A1 - Li, Man A1 - Mijatovic, Vladan A1 - Nolte, Ilja M A1 - Cocca, Massimiliano A1 - Taliun, Daniel A1 - Gomez, Felicia A1 - Li, Yong A1 - Tayo, Bamidele A1 - Tin, Adrienne A1 - Feitosa, Mary F A1 - Aspelund, Thor A1 - Attia, John A1 - Biffar, Reiner A1 - Bochud, Murielle A1 - Boerwinkle, Eric A1 - Borecki, Ingrid A1 - Bottinger, Erwin P A1 - Chen, Ming-Huei A1 - Chouraki, Vincent A1 - Ciullo, Marina A1 - Coresh, Josef A1 - Cornelis, Marilyn C A1 - Curhan, Gary C A1 - d'Adamo, Adamo Pio A1 - Dehghan, Abbas A1 - Dengler, Laura A1 - Ding, Jingzhong A1 - Eiriksdottir, Gudny A1 - Endlich, Karlhans A1 - Enroth, Stefan A1 - Esko, Tõnu A1 - Franco, Oscar H A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Girotto, Giorgia A1 - Gottesman, Omri A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Hancock, Stephen J A1 - Harris, Tamara B A1 - Helmer, Catherine A1 - Höllerer, Simon A1 - Hofer, Edith A1 - Hofman, Albert A1 - Holliday, Elizabeth G A1 - Homuth, Georg A1 - Hu, Frank B A1 - Huth, Cornelia A1 - Hutri-Kähönen, Nina A1 - Hwang, Shih-Jen A1 - Imboden, Medea A1 - Johansson, Åsa A1 - Kähönen, Mika A1 - König, Wolfgang A1 - Kramer, Holly A1 - Krämer, Bernhard K A1 - Kumar, Ashish A1 - Kutalik, Zoltán A1 - Lambert, Jean-Charles A1 - Launer, Lenore J A1 - Lehtimäki, Terho A1 - de Borst, Martin A1 - Navis, Gerjan A1 - Swertz, Morris A1 - Liu, Yongmei A1 - Lohman, Kurt A1 - Loos, Ruth J F A1 - Lu, Yingchang A1 - Lyytikäinen, Leo-Pekka A1 - McEvoy, Mark A A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Metzger, Marie A1 - Mihailov, Evelin A1 - Mitchell, Paul A1 - Nauck, Matthias A1 - Oldehinkel, Albertine J A1 - Olden, Matthias A1 - Wjh Penninx, Brenda A1 - Pistis, Giorgio A1 - Pramstaller, Peter P A1 - Probst-Hensch, Nicole A1 - Raitakari, Olli T A1 - Rettig, Rainer A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Robino, Antonietta A1 - Rosas, Sylvia E A1 - Ruderfer, Douglas A1 - Ruggiero, Daniela A1 - Saba, Yasaman A1 - Sala, Cinzia A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Scott, Rodney J A1 - Sedaghat, Sanaz A1 - Smith, Albert V A1 - Sorice, Rossella A1 - Stengel, Bénédicte A1 - Stracke, Sylvia A1 - Strauch, Konstantin A1 - Toniolo, Daniela A1 - Uitterlinden, André G A1 - Ulivi, Sheila A1 - Viikari, Jorma S A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Völzke, Henry A1 - Vuckovic, Dragana A1 - Waldenberger, Melanie A1 - Jin Wang, Jie A1 - Yang, Qiong A1 - Chasman, Daniel I A1 - Tromp, Gerard A1 - Snieder, Harold A1 - Heid, Iris M A1 - Fox, Caroline S A1 - Köttgen, Anna A1 - Pattaro, Cristian A1 - Böger, Carsten A A1 - Fuchsberger, Christian KW - Computational Biology KW - Gene Frequency KW - Genetic Loci KW - Genome, Human KW - Genome-Wide Association Study KW - Genotyping Techniques KW - Humans KW - Kidney KW - Polymorphism, Single Nucleotide AB -

HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.

VL - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28452372?dopt=Abstract ER - TY - JOUR T1 - and Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function. JF - J Am Soc Nephrol Y1 - 2017 A1 - Li, Man A1 - Li, Yong A1 - Weeks, Olivia A1 - Mijatovic, Vladan A1 - Teumer, Alexander A1 - Huffman, Jennifer E A1 - Tromp, Gerard A1 - Fuchsberger, Christian A1 - Gorski, Mathias A1 - Lyytikäinen, Leo-Pekka A1 - Nutile, Teresa A1 - Sedaghat, Sanaz A1 - Sorice, Rossella A1 - Tin, Adrienne A1 - Yang, Qiong A1 - Ahluwalia, Tarunveer S A1 - Arking, Dan E A1 - Bihlmeyer, Nathan A A1 - Böger, Carsten A A1 - Carroll, Robert J A1 - Chasman, Daniel I A1 - Cornelis, Marilyn C A1 - Dehghan, Abbas A1 - Faul, Jessica D A1 - Feitosa, Mary F A1 - Gambaro, Giovanni A1 - Gasparini, Paolo A1 - Giulianini, Franco A1 - Heid, Iris A1 - Huang, Jinyan A1 - Imboden, Medea A1 - Jackson, Anne U A1 - Jeff, Janina A1 - Jhun, Min A A1 - Katz, Ronit A1 - Kifley, Annette A1 - Kilpeläinen, Tuomas O A1 - Kumar, Ashish A1 - Laakso, Markku A1 - Li-Gao, Ruifang A1 - Lohman, Kurt A1 - Lu, Yingchang A1 - Mägi, Reedik A1 - Malerba, Giovanni A1 - Mihailov, Evelin A1 - Mohlke, Karen L A1 - Mook-Kanamori, Dennis O A1 - Robino, Antonietta A1 - Ruderfer, Douglas A1 - Salvi, Erika A1 - Schick, Ursula M A1 - Schulz, Christina-Alexandra A1 - Smith, Albert V A1 - Smith, Jennifer A A1 - Traglia, Michela A1 - Yerges-Armstrong, Laura M A1 - Zhao, Wei A1 - Goodarzi, Mark O A1 - Kraja, Aldi T A1 - Liu, Chunyu A1 - Wessel, Jennifer A1 - Boerwinkle, Eric A1 - Borecki, Ingrid B A1 - Bork-Jensen, Jette A1 - Bottinger, Erwin P A1 - Braga, Daniele A1 - Brandslund, Ivan A1 - Brody, Jennifer A A1 - Campbell, Archie A1 - Carey, David J A1 - Christensen, Cramer A1 - Coresh, Josef A1 - Crook, Errol A1 - Curhan, Gary C A1 - Cusi, Daniele A1 - de Boer, Ian H A1 - de Vries, Aiko P J A1 - Denny, Joshua C A1 - Devuyst, Olivier A1 - Dreisbach, Albert W A1 - Endlich, Karlhans A1 - Esko, Tõnu A1 - Franco, Oscar H A1 - Fulop, Tibor A1 - Gerhard, Glenn S A1 - Glümer, Charlotte A1 - Gottesman, Omri A1 - Grarup, Niels A1 - Gudnason, Vilmundur A1 - Hansen, Torben A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Hocking, Lynne A1 - Hofman, Albert A1 - Hu, Frank B A1 - Husemoen, Lise Lotte N A1 - Jackson, Rebecca D A1 - Jørgensen, Torben A1 - Jørgensen, Marit E A1 - Kähönen, Mika A1 - Kardia, Sharon L R A1 - König, Wolfgang A1 - Kooperberg, Charles A1 - Kriebel, Jennifer A1 - Launer, Lenore J A1 - Lauritzen, Torsten A1 - Lehtimäki, Terho A1 - Levy, Daniel A1 - Linksted, Pamela A1 - Linneberg, Allan A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Lupo, Antonio A1 - Meisinger, Christine A1 - Melander, Olle A1 - Metspalu, Andres A1 - Mitchell, Paul A1 - Nauck, Matthias A1 - Nürnberg, Peter A1 - Orho-Melander, Marju A1 - Parsa, Afshin A1 - Pedersen, Oluf A1 - Peters, Annette A1 - Peters, Ulrike A1 - Polasek, Ozren A1 - Porteous, David A1 - Probst-Hensch, Nicole M A1 - Psaty, Bruce M A1 - Qi, Lu A1 - Raitakari, Olli T A1 - Reiner, Alex P A1 - Rettig, Rainer A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rossouw, Jacques E A1 - Schmidt, Frank A1 - Siscovick, David A1 - Soranzo, Nicole A1 - Strauch, Konstantin A1 - Toniolo, Daniela A1 - Turner, Stephen T A1 - Uitterlinden, André G A1 - Ulivi, Sheila A1 - Velayutham, Dinesh A1 - Völker, Uwe A1 - Völzke, Henry A1 - Waldenberger, Melanie A1 - Wang, Jie Jin A1 - Weir, David R A1 - Witte, Daniel A1 - Kuivaniemi, Helena A1 - Fox, Caroline S A1 - Franceschini, Nora A1 - Goessling, Wolfram A1 - Köttgen, Anna A1 - Chu, Audrey Y KW - Animals KW - Exome KW - Genetic Loci KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Protein Tyrosine Phosphatases KW - Proto-Oncogene Proteins KW - Son of Sevenless Proteins KW - Zebrafish AB -

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (: 111,666; : 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (, , and ; <3.7×10), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, (=5.4×10 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of and -knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

VL - 28 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27920155?dopt=Abstract ER - TY - JOUR T1 - Child and Adolescent Health From 1990 to 2015: Findings From the Global Burden of Diseases, Injuries, and Risk Factors 2015 Study. JF - JAMA Pediatr Y1 - 2017 A1 - Kassebaum, Nicholas A1 - Kyu, Hmwe Hmwe A1 - Zoeckler, Leo A1 - Olsen, Helen Elizabeth A1 - Thomas, Katie A1 - Pinho, Christine A1 - Bhutta, Zulfiqar A A1 - Dandona, Lalit A1 - Ferrari, Alize A1 - Ghiwot, Tsegaye Tewelde A1 - Hay, Simon I A1 - Kinfu, Yohannes A1 - Liang, Xiaofeng A1 - Lopez, Alan A1 - Malta, Deborah Carvalho A1 - Mokdad, Ali H A1 - Naghavi, Mohsen A1 - Patton, George C A1 - Salomon, Joshua A1 - Sartorius, Benn A1 - Topor-Madry, Roman A1 - Vollset, Stein Emil A1 - Werdecker, Andrea A1 - Whiteford, Harvey A A1 - Abate, Kalkidan Hasen A1 - Abbas, Kaja A1 - Damtew, Solomon Abrha A1 - Ahmed, Muktar Beshir A1 - Akseer, Nadia A1 - Al-Raddadi, Rajaa A1 - Alemayohu, Mulubirhan Assefa A1 - Altirkawi, Khalid A1 - Abajobir, Amanuel Alemu A1 - Amare, Azmeraw T A1 - Antonio, Carl A T A1 - Arnlöv, Johan A1 - Artaman, Al A1 - Asayesh, Hamid A1 - Avokpaho, Euripide Frinel G Arthur A1 - Awasthi, Ashish A1 - Ayala Quintanilla, Beatriz Paulina A1 - Bacha, Umar A1 - Betsu, Balem Demtsu A1 - Barac, Aleksandra A1 - Bärnighausen, Till Winfried A1 - Baye, Estifanos A1 - Bedi, Neeraj A1 - Bensenor, Isabela M A1 - Berhane, Adugnaw A1 - Bernabe, Eduardo A1 - Bernal, Oscar Alberto A1 - Beyene, Addisu Shunu A1 - Biadgilign, Sibhatu A1 - Bikbov, Boris A1 - Boyce, Cheryl Anne A1 - Brazinova, Alexandra A1 - Hailu, Gessessew Bugssa A1 - Carter, Austin A1 - Castañeda-Orjuela, Carlos A A1 - Catalá-López, Ferrán A1 - Charlson, Fiona J A1 - Chitheer, Abdulaal A A1 - Choi, Jee-Young Jasmine A1 - Ciobanu, Liliana G A1 - Crump, John A1 - Dandona, Rakhi A1 - Dellavalle, Robert P A1 - Deribew, Amare A1 - deVeber, Gabrielle A1 - Dicker, Daniel A1 - Ding, Eric L A1 - Dubey, Manisha A1 - Endries, Amanuel Yesuf A1 - Erskine, Holly E A1 - Faraon, Emerito Jose Aquino A1 - Faro, Andre A1 - Farzadfar, Farshad A1 - Fernandes, Joao C A1 - Fijabi, Daniel Obadare A1 - Fitzmaurice, Christina A1 - Fleming, Thomas D A1 - Flor, Luisa Sorio A1 - Foreman, Kyle J A1 - Franklin, Richard C A1 - Fraser, Maya S A1 - Frostad, Joseph J A1 - Fullman, Nancy A1 - Gebregergs, Gebremedhin Berhe A1 - Gebru, Alemseged Aregay A1 - Geleijnse, Johanna M A1 - Gibney, Katherine B A1 - Gidey Yihdego, Mahari A1 - Ginawi, Ibrahim Abdelmageem Mohamed A1 - Gishu, Melkamu Dedefo A1 - Gizachew, Tessema Assefa A1 - Glaser, Elizabeth A1 - Gold, Audra L A1 - Goldberg, Ellen A1 - Gona, Philimon A1 - Goto, Atsushi A1 - Gugnani, Harish Chander A1 - Jiang, Guohong A1 - Gupta, Rajeev A1 - Tesfay, Fisaha Haile A1 - Hankey, Graeme J A1 - Havmoeller, Rasmus A1 - Hijar, Martha A1 - Horino, Masako A1 - Hosgood, H Dean A1 - Hu, Guoqing A1 - Jacobsen, Kathryn H A1 - Jakovljevic, Mihajlo B A1 - Jayaraman, Sudha P A1 - Jha, Vivekanand A1 - Jibat, Tariku A1 - Johnson, Catherine O A1 - Jonas, Jost A1 - Kasaeian, Amir A1 - Kawakami, Norito A1 - Keiyoro, Peter N A1 - Khalil, Ibrahim A1 - Khang, Young-Ho A1 - Khubchandani, Jagdish A1 - Ahmad Kiadaliri, Aliasghar A A1 - Kieling, Christian A1 - Kim, Daniel A1 - Kissoon, Niranjan A1 - Knibbs, Luke D A1 - Koyanagi, Ai A1 - Krohn, Kristopher J A1 - Kuate Defo, Barthelemy A1 - Kucuk Bicer, Burcu A1 - Kulikoff, Rachel A1 - Kumar, G Anil A1 - Lal, Dharmesh Kumar A1 - Lam, Hilton Y A1 - Larson, Heidi J A1 - Larsson, Anders A1 - Laryea, Dennis Odai A1 - Leung, Janni A1 - Lim, Stephen S A1 - Lo, Loon-Tzian A1 - Lo, Warren D A1 - Looker, Katharine J A1 - Lotufo, Paulo A A1 - Magdy Abd El Razek, Hassan A1 - Malekzadeh, Reza A1 - Markos Shifti, Desalegn A1 - Mazidi, Mohsen A1 - Meaney, Peter A A1 - Meles, Kidanu Gebremariam A1 - Memiah, Peter A1 - Mendoza, Walter A1 - Abera Mengistie, Mubarek A1 - Mengistu, Gebremichael Welday A1 - Mensah, George A A1 - Miller, Ted R A1 - Mock, Charles A1 - Mohammadi, Alireza A1 - Mohammed, Shafiu A1 - Monasta, Lorenzo A1 - Mueller, Ulrich A1 - Nagata, Chie A1 - Naheed, Aliya A1 - Nguyen, Grant A1 - Nguyen, Quyen Le A1 - Nsoesie, Elaine A1 - Oh, In-Hwan A1 - Okoro, Anselm A1 - Olusanya, Jacob Olusegun A1 - Olusanya, Bolajoko O A1 - Ortiz, Alberto A1 - Paudel, Deepak A1 - Pereira, David M A1 - Perico, Norberto A1 - Petzold, Max A1 - Phillips, Michael Robert A1 - Polanczyk, Guilherme V A1 - Pourmalek, Farshad A1 - Qorbani, Mostafa A1 - Rafay, Anwar A1 - Rahimi-Movaghar, Vafa A1 - Rahman, Mahfuzar A1 - Rai, Rajesh Kumar A1 - Ram, Usha A1 - Rankin, Zane A1 - Remuzzi, Giuseppe A1 - Renzaho, Andre M N A1 - Roba, Hirbo Shore A1 - Rojas-Rueda, David A1 - Ronfani, Luca A1 - Sagar, Rajesh A1 - Sanabria, Juan Ramon A1 - Kedir Mohammed, Muktar Sano A1 - Santos, Itamar S A1 - Satpathy, Maheswar A1 - Sawhney, Monika A1 - Schöttker, Ben A1 - Schwebel, David C A1 - Scott, James G A1 - Sepanlou, Sadaf G A1 - Shaheen, Amira A1 - Shaikh, Masood Ali A1 - She, June A1 - Shiri, Rahman A1 - Shiue, Ivy A1 - Sigfusdottir, Inga Dora A1 - Singh, Jasvinder A1 - Silpakit, Naris A1 - Smith, Alison A1 - Sreeramareddy, Chandrashekhar A1 - Stanaway, Jeffrey D A1 - Stein, Dan J A1 - Steiner, Caitlyn A1 - Sufiyan, Muawiyyah Babale A1 - Swaminathan, Soumya A1 - Tabarés-Seisdedos, Rafael A1 - Tabb, Karen M A1 - Tadese, Fentaw A1 - Tavakkoli, Mohammad A1 - Taye, Bineyam A1 - Teeple, Stephanie A1 - Tegegne, Teketo Kassaw A1 - Temam Shifa, Girma A1 - Terkawi, Abdullah Sulieman A1 - Thomas, Bernadette A1 - Thomson, Alan J A1 - Tobe-Gai, Ruoyan A1 - Tonelli, Marcello A1 - Tran, Bach Xuan A1 - Troeger, Christopher A1 - Ukwaja, Kingsley N A1 - Uthman, Olalekan A1 - Vasankari, Tommi A1 - Venketasubramanian, Narayanaswamy A1 - Vlassov, Vasiliy Victorovich A1 - Weiderpass, Elisabete A1 - Weintraub, Robert A1 - Gebrehiwot, Solomon Weldemariam A1 - Westerman, Ronny A1 - Williams, Hywel C A1 - Wolfe, Charles D A A1 - Woodbrook, Rachel A1 - Yano, Yuichiro A1 - Yonemoto, Naohiro A1 - Yoon, Seok-Jun A1 - Younis, Mustafa Z A1 - Yu, Chuanhua A1 - Zaki, Maysaa El Sayed A1 - Zegeye, Elias Asfaw A1 - Zuhlke, Liesl Joanna A1 - Murray, Christopher J L A1 - Vos, Theo KW - Adolescent KW - Adolescent Health KW - Age Factors KW - Cause of Death KW - Child KW - Child Health KW - Child Mortality KW - Disabled Children KW - Female KW - Global Burden of Disease KW - Global Health KW - Humans KW - Male KW - Pregnancy KW - Pregnancy Complications KW - Risk Factors KW - Sex Factors KW - Wounds and Injuries AB -

Importance: Comprehensive and timely monitoring of disease burden in all age groups, including children and adolescents, is essential for improving population health.

Objective: To quantify and describe levels and trends of mortality and nonfatal health outcomes among children and adolescents from 1990 to 2015 to provide a framework for policy discussion.

Evidence Review: Cause-specific mortality and nonfatal health outcomes were analyzed for 195 countries and territories by age group, sex, and year from 1990 to 2015 using standardized approaches for data processing and statistical modeling, with subsequent analysis of the findings to describe levels and trends across geography and time among children and adolescents 19 years or younger. A composite indicator of income, education, and fertility was developed (Socio-demographic Index [SDI]) for each geographic unit and year, which evaluates the historical association between SDI and health loss.

Findings: Global child and adolescent mortality decreased from 14.18 million (95% uncertainty interval [UI], 14.09 million to 14.28 million) deaths in 1990 to 7.26 million (95% UI, 7.14 million to 7.39 million) deaths in 2015, but progress has been unevenly distributed. Countries with a lower SDI had a larger proportion of mortality burden (75%) in 2015 than was the case in 1990 (61%). Most deaths in 2015 occurred in South Asia and sub-Saharan Africa. Global trends were driven by reductions in mortality owing to infectious, nutritional, and neonatal disorders, which in the aggregate led to a relative increase in the importance of noncommunicable diseases and injuries in explaining global disease burden. The absolute burden of disability in children and adolescents increased 4.3% (95% UI, 3.1%-5.6%) from 1990 to 2015, with much of the increase owing to population growth and improved survival for children and adolescents to older ages. Other than infectious conditions, many top causes of disability are associated with long-term sequelae of conditions present at birth (eg, neonatal disorders, congenital birth defects, and hemoglobinopathies) and complications of a variety of infections and nutritional deficiencies. Anemia, developmental intellectual disability, hearing loss, epilepsy, and vision loss are important contributors to childhood disability that can arise from multiple causes. Maternal and reproductive health remains a key cause of disease burden in adolescent females, especially in lower-SDI countries. In low-SDI countries, mortality is the primary driver of health loss for children and adolescents, whereas disability predominates in higher-SDI locations; the specific pattern of epidemiological transition varies across diseases and injuries.

Conclusions and Relevance: Consistent international attention and investment have led to sustained improvements in causes of health loss among children and adolescents in many countries, although progress has been uneven. The persistence of infectious diseases in some countries, coupled with ongoing epidemiologic transition to injuries and noncommunicable diseases, require all countries to carefully evaluate and implement appropriate strategies to maximize the health of their children and adolescents and for the international community to carefully consider which elements of child and adolescent health should be monitored.

VL - 171 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28384795?dopt=Abstract ER - TY - JOUR T1 - Combined use of AFM and soft X-ray microscopy to reveal fibres' internalization in mesothelial cells. JF - Analyst Y1 - 2017 A1 - Gianoncelli, Alessandra A1 - Kourousias, George A1 - Cammisuli, Francesca A1 - Cassese, Damiano A1 - Rizzardi, Clara A1 - Radillo, Oriano A1 - Lazzarino, Marco A1 - Pascolo, Lorella KW - Asbestos KW - Cell Line KW - Epithelial Cells KW - Epithelium KW - Humans KW - Microscopy, Atomic Force KW - X-Rays AB -

Nanotoxicology and nanomedicine investigations often require the probing of nano-objects such as fibres and particles in biological samples and cells, whilst internalization and intracellular destiny are the main issues for in vitro cellular studies. Various high resolution microscopy techniques are well suited for providing this highly sought-after information. However, sample preparation, nanomaterial composition and sectioning challenges make it often difficult to establish whether the fibres or particles have been internalized or they are simply overlaying or underlying the biological matter. In this paper we suggest a novel suitable combination of two different microscopic techniques to reveal in intact cells the uptake of asbestos fibres by mesothelial cells. After exposure to asbestos fibres and fixation, cells were first analysed under the AFM instrument and then imaged under the TwinMic soft X-ray microscope at Elettra Sincrotrone. The suggested approach combines standard soft X-ray microscopy imaging and AFM microscopy, with a common non-invasive sample preparation protocol which drastically reduces the experimental uncertainty and provides a quick and definitive answer to the nanoparticle cellular and tissue uptake.

VL - 142 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28509933?dopt=Abstract ER - TY - JOUR T1 - Complement Protein C1q Binds to Hyaluronic Acid in the Malignant Pleural Mesothelioma Microenvironment and Promotes Tumor Growth. JF - Front Immunol Y1 - 2017 A1 - Agostinis, Chiara A1 - Vidergar, Romana A1 - Belmonte, Beatrice A1 - Mangogna, Alessandro A1 - Amadio, Leonardo A1 - Geri, Pietro A1 - Borelli, Violetta A1 - Zanconati, Fabrizio A1 - Tedesco, Francesco A1 - Confalonieri, Marco A1 - Tripodo, Claudio A1 - Kishore, Uday A1 - Bulla, Roberta AB -

C1q is the first recognition subcomponent of the complement classical pathway, which acts toward the clearance of pathogens and apoptotic cells. C1q is also known to modulate a range of functions of immune and non-immune cells, and has been shown to be involved in placental development and sensorial synaptic pruning. We have recently shown that C1q can promote tumor by encouraging their adhesion, migration, and proliferation in addition to angiogenesis and metastasis. In this study, we have examined the role of human C1q in the microenvironment of malignant pleural mesothelioma (MPM), a rare form of cancer commonly associated with exposure to asbestos. We found that C1q was highly expressed in all MPM histotypes, particularly in epithelioid rather than in sarcomatoid histotype. C1q avidly bound high and low molecular weight hyaluronic acid (HA) its globular domain. C1q bound to HA was able to induce adhesion and proliferation of mesothelioma cells (MES) enhancement of ERK1/2, SAPK/JNK, and p38 phosphorylation; however, it did not activate the complement cascade. Consistent with the modular organization of the globular domain, we demonstrated that C1q may bind to HA through ghA module, whereas it may interact with human MES through the ghC. In conclusion, C1q highly expressed in MPM binds to HA and enhances the tumor growth promoting cell adhesion and proliferation. These data can help develop novel diagnostic markers and molecular targets for MPM.

VL - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29209316?dopt=Abstract ER - TY - JOUR T1 - Factors Influencing the Phenotypic Characterization of the Oral Marker, PROP. JF - Nutrients Y1 - 2017 A1 - Tepper, Beverly J A1 - Melis, Melania A1 - Koelliker, Yvonne A1 - Gasparini, Paolo A1 - Ahijevych, Karen L A1 - Tomassini Barbarossa, Iole KW - Food Preferences KW - Genetic Variation KW - Humans KW - Propylthiouracil KW - Taste Perception KW - Taste Threshold AB -

In the last several decades, the genetic ability to taste the bitter compound, 6--propyltiouracil (PROP) has attracted considerable attention as a model for understanding individual differences in taste perception, and as an oral marker for food preferences and eating behavior that ultimately impacts nutritional status and health. However, some studies do not support this role. This review describes common factors that can influence the characterization of this phenotype including: (1) changes in taste sensitivity with increasing age; (2) gender differences in taste perception; and (3) effects of smoking and obesity. We suggest that attention to these factors during PROP screening could strengthen the associations between this phenotype and a variety of health outcomes ranging from variation in body composition to oral health and cancer risk.

VL - 9 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29168731?dopt=Abstract ER - TY - JOUR T1 - Genetic structure in the Sherpa and neighboring Nepalese populations. JF - BMC Genomics Y1 - 2017 A1 - Cole, Amy M A1 - Cox, Sean A1 - Jeong, Choongwon A1 - Petousi, Nayia A1 - Aryal, Dhana R A1 - Droma, Yunden A1 - Hanaoka, Masayuki A1 - Ota, Masao A1 - Kobayashi, Nobumitsu A1 - Gasparini, Paolo A1 - Montgomery, Hugh A1 - Robbins, Peter A1 - Di Rienzo, Anna A1 - Cavalleri, Gianpiero L KW - Asian Continental Ancestry Group KW - Chromosomes, Human, Y KW - DNA KW - DNA, Mitochondrial KW - Ethnic Groups KW - Gene Flow KW - Genotype KW - Humans KW - Leukocytes KW - Likelihood Functions KW - Nepal KW - Principal Component Analysis AB -

BACKGROUND: We set out to describe the fine-scale population structure across the Eastern region of Nepal. To date there is relatively little known about the genetic structure of the Sherpa residing in Nepal and their genetic relationship with the Nepalese. We assembled dense genotype data from a total of 1245 individuals representing Nepal and a variety of different populations resident across the greater Himalayan region including Tibet, China, India, Pakistan, Kazakhstan, Uzbekistan, Tajikistan and Kirghizstan. We performed analysis of principal components, admixture and homozygosity.

RESULTS: We identified clear substructure across populations resident in the Himalayan arc, with genetic structure broadly mirroring geographical features of the region. Ethnic subgroups within Nepal show distinct genetic structure, on both admixture and principal component analysis. We detected differential proportions of ancestry from northern Himalayan populations across Nepalese subgroups, with the Nepalese Rai, Magar and Tamang carrying the greatest proportions of Tibetan ancestry.

CONCLUSIONS: We show that populations dwelling on the Himalayan plateau have had a clear impact on the Northern Indian gene pool. We illustrate how the Sherpa are a remarkably isolated population, with little gene flow from surrounding Nepalese populations.

VL - 18 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28103797?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk. JF - Nat Genet Y1 - 2017 A1 - Warren, Helen R A1 - Evangelou, Evangelos A1 - Cabrera, Claudia P A1 - Gao, He A1 - Ren, Meixia A1 - Mifsud, Borbala A1 - Ntalla, Ioanna A1 - Surendran, Praveen A1 - Liu, Chunyu A1 - Cook, James P A1 - Kraja, Aldi T A1 - Drenos, Fotios A1 - Loh, Marie A1 - Verweij, Niek A1 - Marten, Jonathan A1 - Karaman, Ibrahim A1 - Lepe, Marcelo P Segura A1 - O'Reilly, Paul F A1 - Knight, Joanne A1 - Snieder, Harold A1 - Kato, Norihiro A1 - He, Jiang A1 - Tai, E Shyong A1 - Said, M Abdullah A1 - Porteous, David A1 - Alver, Maris A1 - Poulter, Neil A1 - Farrall, Martin A1 - Gansevoort, Ron T A1 - Padmanabhan, Sandosh A1 - Mägi, Reedik A1 - Stanton, Alice A1 - Connell, John A1 - Bakker, Stephan J L A1 - Metspalu, Andres A1 - Shields, Denis C A1 - Thom, Simon A1 - Brown, Morris A1 - Sever, Peter A1 - Esko, Tõnu A1 - Hayward, Caroline A1 - van der Harst, Pim A1 - Saleheen, Danish A1 - Chowdhury, Rajiv A1 - Chambers, John C A1 - Chasman, Daniel I A1 - Chakravarti, Aravinda A1 - Newton-Cheh, Christopher A1 - Lindgren, Cecilia M A1 - Levy, Daniel A1 - Kooner, Jaspal S A1 - Keavney, Bernard A1 - Tomaszewski, Maciej A1 - Samani, Nilesh J A1 - Howson, Joanna M M A1 - Tobin, Martin D A1 - Munroe, Patricia B A1 - Ehret, Georg B A1 - Wain, Louise V KW - Adult KW - Blood Pressure KW - Cardiovascular Diseases KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk.

VL - 49 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28135244?dopt=Abstract ER - TY - JOUR T1 - Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. JF - Nat Genet Y1 - 2017 A1 - Day, Felix R A1 - Thompson, Deborah J A1 - Helgason, Hannes A1 - Chasman, Daniel I A1 - Finucane, Hilary A1 - Sulem, Patrick A1 - Ruth, Katherine S A1 - Whalen, Sean A1 - Sarkar, Abhishek K A1 - Albrecht, Eva A1 - Altmaier, Elisabeth A1 - Amini, Marzyeh A1 - Barbieri, Caterina M A1 - Boutin, Thibaud A1 - Campbell, Archie A1 - Demerath, Ellen A1 - Giri, Ayush A1 - He, Chunyan A1 - Hottenga, Jouke J A1 - Karlsson, Robert A1 - Kolcic, Ivana A1 - Loh, Po-Ru A1 - Lunetta, Kathryn L A1 - Mangino, Massimo A1 - Marco, Brumat A1 - McMahon, George A1 - Medland, Sarah E A1 - Nolte, Ilja M A1 - Noordam, Raymond A1 - Nutile, Teresa A1 - Paternoster, Lavinia A1 - Perjakova, Natalia A1 - Porcu, Eleonora A1 - Rose, Lynda M A1 - Schraut, Katharina E A1 - Segrè, Ayellet V A1 - Smith, Albert V A1 - Stolk, Lisette A1 - Teumer, Alexander A1 - Andrulis, Irene L A1 - Bandinelli, Stefania A1 - Beckmann, Matthias W A1 - Benitez, Javier A1 - Bergmann, Sven A1 - Bochud, Murielle A1 - Boerwinkle, Eric A1 - Bojesen, Stig E A1 - Bolla, Manjeet K A1 - Brand, Judith S A1 - Brauch, Hiltrud A1 - Brenner, Hermann A1 - Broer, Linda A1 - Brüning, Thomas A1 - Buring, Julie E A1 - Campbell, Harry A1 - Catamo, Eulalia A1 - Chanock, Stephen A1 - Chenevix-Trench, Georgia A1 - Corre, Tanguy A1 - Couch, Fergus J A1 - Cousminer, Diana L A1 - Cox, Angela A1 - Crisponi, Laura A1 - Czene, Kamila A1 - Davey Smith, George A1 - de Geus, Eco J C N A1 - de Mutsert, Renée A1 - De Vivo, Immaculata A1 - Dennis, Joe A1 - Devilee, Peter A1 - Dos-Santos-Silva, Isabel A1 - Dunning, Alison M A1 - Eriksson, Johan G A1 - Fasching, Peter A A1 - Fernández-Rhodes, Lindsay A1 - Ferrucci, Luigi A1 - Flesch-Janys, Dieter A1 - Franke, Lude A1 - Gabrielson, Marike A1 - Gandin, Ilaria A1 - Giles, Graham G A1 - Grallert, Harald A1 - Gudbjartsson, Daniel F A1 - Guenel, Pascal A1 - Hall, Per A1 - Hallberg, Emily A1 - Hamann, Ute A1 - Harris, Tamara B A1 - Hartman, Catharina A A1 - Heiss, Gerardo A1 - Hooning, Maartje J A1 - Hopper, John L A1 - Hu, Frank A1 - Hunter, David J A1 - Ikram, M Arfan A1 - Im, Hae Kyung A1 - Järvelin, Marjo-Riitta A1 - Joshi, Peter K A1 - Karasik, David A1 - Kellis, Manolis A1 - Kutalik, Zoltán A1 - LaChance, Genevieve A1 - Lambrechts, Diether A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Laven, Joop S E A1 - Lenarduzzi, Stefania A1 - Li, Jingmei A1 - Lind, Penelope A A1 - Lindström, Sara A1 - Liu, Yongmei A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Mannermaa, Arto A1 - Mbarek, Hamdi A1 - McCarthy, Mark I A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Menni, Cristina A1 - Metspalu, Andres A1 - Michailidou, Kyriaki A1 - Milani, Lili A1 - Milne, Roger L A1 - Montgomery, Grant W A1 - Mulligan, Anna M A1 - Nalls, Mike A A1 - Navarro, Pau A1 - Nevanlinna, Heli A1 - Nyholt, Dale R A1 - Oldehinkel, Albertine J A1 - O'Mara, Tracy A A1 - Padmanabhan, Sandosh A1 - Palotie, Aarno A1 - Pedersen, Nancy A1 - Peters, Annette A1 - Peto, Julian A1 - Pharoah, Paul D P A1 - Pouta, Anneli A1 - Radice, Paolo A1 - Rahman, Iffat A1 - Ring, Susan M A1 - Robino, Antonietta A1 - Rosendaal, Frits R A1 - Rudan, Igor A1 - Rueedi, Rico A1 - Ruggiero, Daniela A1 - Sala, Cinzia F A1 - Schmidt, Marjanka K A1 - Scott, Robert A A1 - Shah, Mitul A1 - Sorice, Rossella A1 - Southey, Melissa C A1 - Sovio, Ulla A1 - Stampfer, Meir A1 - Steri, Maristella A1 - Strauch, Konstantin A1 - Tanaka, Toshiko A1 - Tikkanen, Emmi A1 - Timpson, Nicholas J A1 - Traglia, Michela A1 - Truong, Therese A1 - Tyrer, Jonathan P A1 - Uitterlinden, André G A1 - Edwards, Digna R Velez A1 - Vitart, Veronique A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Wang, Qin A1 - Widen, Elisabeth A1 - van Dijk, Ko Willems A1 - Willemsen, Gonneke A1 - Winqvist, Robert A1 - Wolffenbuttel, Bruce H R A1 - Zhao, Jing Hua A1 - Zoledziewska, Magdalena A1 - Zygmunt, Marek A1 - Alizadeh, Behrooz Z A1 - Boomsma, Dorret I A1 - Ciullo, Marina A1 - Cucca, Francesco A1 - Esko, Tõnu A1 - Franceschini, Nora A1 - Gieger, Christian A1 - Gudnason, Vilmundur A1 - Hayward, Caroline A1 - Kraft, Peter A1 - Lawlor, Debbie A A1 - Magnusson, Patrik K E A1 - Martin, Nicholas G A1 - Mook-Kanamori, Dennis O A1 - Nohr, Ellen A A1 - Polasek, Ozren A1 - Porteous, David A1 - Price, Alkes L A1 - Ridker, Paul M A1 - Snieder, Harold A1 - Spector, Tim D A1 - Stöckl, Doris A1 - Toniolo, Daniela A1 - Ulivi, Sheila A1 - Visser, Jenny A A1 - Völzke, Henry A1 - Wareham, Nicholas J A1 - Wilson, James F A1 - Spurdle, Amanda B A1 - Thorsteindottir, Unnur A1 - Pollard, Katherine S A1 - Easton, Douglas F A1 - Tung, Joyce Y A1 - Chang-Claude, Jenny A1 - Hinds, David A1 - Murray, Anna A1 - Murabito, Joanne M A1 - Stefansson, Kari A1 - Ong, Ken K A1 - Perry, John R B KW - Adolescent KW - Age Factors KW - Body Mass Index KW - Databases, Genetic KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genomic Imprinting KW - Humans KW - Intercellular Signaling Peptides and Proteins KW - Male KW - Membrane Proteins KW - Menarche KW - Neoplasms KW - Polymorphism, Single Nucleotide KW - Puberty KW - Quantitative Trait Loci KW - Ribonucleoproteins KW - Risk Factors AB -

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

VL - 49 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28436984?dopt=Abstract ER - TY - JOUR T1 - Impact of the 13-Valent Pneumococcal Conjugate Vaccine on Clinical and Hypoxemic Childhood Pneumonia over Three Years in Central Malawi: An Observational Study. JF - PLoS One Y1 - 2017 A1 - McCollum, Eric D A1 - Nambiar, Bejoy A1 - Deula, Rashid A1 - Zadutsa, Beatiwel A1 - Bondo, Austin A1 - King, Carina A1 - Beard, James A1 - Liyaya, Harry A1 - Mankhambo, Limangeni A1 - Lazzerini, Marzia A1 - Makwenda, Charles A1 - Masache, Gibson A1 - Bar-Zeev, Naor A1 - Kazembe, Peter N A1 - Mwansambo, Charles A1 - Lufesi, Norman A1 - Costello, Anthony A1 - Armstrong, Ben A1 - Colbourn, Tim KW - Child KW - Child Mortality KW - Cost of Illness KW - Dose-Response Relationship, Immunologic KW - Geography KW - Humans KW - Hypoxia KW - Malawi KW - Pneumococcal Vaccines KW - Pneumonia, Pneumococcal KW - Time Factors KW - Vaccines, Conjugate AB -

BACKGROUND: The pneumococcal conjugate vaccine's (PCV) impact on childhood pneumonia during programmatic conditions in Africa is poorly understood. Following PCV13 introduction in Malawi in November 2011, we evaluated the case burden and rates of childhood pneumonia.

METHODS AND FINDINGS: Between January 1, 2012-June 30, 2014 we conducted active pneumonia surveillance in children <5 years at seven hospitals, 18 health centres, and with 38 community health workers in two districts, central Malawi. Eligible children had clinical pneumonia per Malawi guidelines, defined as fast breathing only, chest indrawing +/- fast breathing, or, ≥1 clinical danger sign. Since pulse oximetry was not in the Malawi guidelines, oxygenation <90% defined hypoxemic pneumonia, a distinct category from clinical pneumonia. We quantified the pneumonia case burden and rates in two ways. We compared the period immediately following vaccine introduction (early) to the period with >75% three-dose PCV13 coverage (post). We also used multivariable time-series regression, adjusting for autocorrelation and exploring seasonal variation and alternative model specifications in sensitivity analyses. The early versus post analysis showed an increase in cases and rates of total, fast breathing, and indrawing pneumonia and a decrease in danger sign and hypoxemic pneumonia, and pneumonia mortality. At 76% three-dose PCV13 coverage, versus 0%, the time-series model showed a non-significant increase in total cases (+47%, 95% CI: -13%, +149%, p = 0.154); fast breathing cases increased 135% (+39%, +297%, p = 0.001), however, hypoxemia fell 47% (-5%, -70%, p = 0.031) and hospital deaths decreased 36% (-1%, -58%, p = 0.047) in children <5 years. We observed a shift towards disease without danger signs, as the proportion of cases with danger signs decreased by 65% (-46%, -77%, p<0.0001). These results were generally robust to plausible alternative model specifications.

CONCLUSIONS: Thirty months after PCV13 introduction in Malawi, the health system burden and rates of the severest forms of childhood pneumonia, including hypoxemia and death, have markedly decreased.

VL - 12 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28052071?dopt=Abstract ER - TY - JOUR T1 - Improving the quality of hospital care for children by supportive supervision: a cluster randomized trial, Kyrgyzstan. JF - Bull World Health Organ Y1 - 2017 A1 - Lazzerini, Marzia A1 - Shukurova, Venera A1 - Davletbaeva, Marina A1 - Monolbaev, Kubanychbek A1 - Kulichenko, Tatiana A1 - Akoev, Yuri A1 - Bakradze, Maya A1 - Margieva, Tea A1 - Mityushino, Ilya A1 - Namazova-Baranova, Leyla A1 - Boronbayeva, Elnura A1 - Kuttumuratova, Aigul A1 - Weber, Martin Willy A1 - Tamburlini, Giorgio KW - Child KW - Child Care KW - Cluster Analysis KW - Hospitalization KW - Hospitals, Public KW - Humans KW - Kyrgyzstan KW - Medical Audit KW - Pediatricians KW - Professional Role KW - Prospective Studies KW - Quality Improvement AB -

OBJECTIVE: To determine whether periodic supportive supervision after a training course improved the quality of paediatric hospital care in Kyrgyzstan, where inappropriate care was common but in-hospital postnatal mortality was low.

METHODS: In a cluster, randomized, parallel-group trial, 10 public hospitals were allocated to a 4-day World Health Organization (WHO) course on hospital care for children followed by periodic supportive supervision by paediatricians for 1 year, while 10 hospitals had no intervention. We assessed prospectively 10 key indicators of inappropriate paediatric case management, as indicated by WHO guidelines. The primary indicator was the combination of the three indicators: unnecessary hospitalization, increased iatrogenic risk and unnecessary painful procedures. An independent team evaluated the overall quality of care.

FINDINGS: We prospectively reviewed the medical records of 4626 hospitalized children aged 2 to 60 months. In the intervention hospitals, the mean proportion of the primary indicator decreased from 46.9% (95% confidence interval, CI: 24.2 to 68.9) at baseline to 6.8% (95% CI: 1.1 to 12.1) at 1 year, but was unchanged in the control group (45.5%, 95% CI: 25.2 to 67.9, to 64.7%, 95% CI: 43.3 to 86.1). At 1 year, the risk ratio for the primary indicator in the intervention versus the control group was 0.09 (95% CI: 0.06 to 0.13). The proportions of the other nine indicators also decreased in the intervention group ( < 0.0001 for all). Overall quality of care improved significantly in intervention hospitals.

CONCLUSION: Periodic supportive supervision for 1 year after a training course improved both adherence to WHO guidelines on hospital care for children and the overall quality of paediatric care.

VL - 95 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28603306?dopt=Abstract ER - TY - JOUR T1 - Introduction of Complementary Foods in a Cohort of Infants in Northeast Italy: Do Parents Comply with WHO Recommendations? JF - Nutrients Y1 - 2017 A1 - Carletti, Claudia A1 - Pani, Paola A1 - Monasta, Lorenzo A1 - Knowles, Alessandra A1 - Cattaneo, Adriano KW - Adult KW - Cohort Studies KW - Dairy Products KW - Diet KW - Edible Grain KW - Female KW - Follow-Up Studies KW - Fruit KW - Humans KW - Infant KW - Infant Nutritional Physiological Phenomena KW - Italy KW - Logistic Models KW - Male KW - Mothers KW - Patient Compliance KW - Recommended Dietary Allowances KW - Socioeconomic Factors KW - Vegetables KW - World Health Organization AB -

Timing and type of complementary food in infancy affect nutritional status and health later in life. The objective of this paper was to assess complementary feeding practices, looking at timing, type, and compliance with World Health Organization (WHO) recommendations. Data were obtained from a birth cohort of 400 infants, enrolled in Trieste (Italy) between July 2007 and July 2008 and followed up for three years, using a "food introduction timing table". Five WHO recommendations standards were used to assess parental compliance and associated factors. Thirty seven percent of mothers returned the completed "timing table" up until the child was three years of age. Eighty six percent of infants were already receiving complementary foods at six months. The first food type to be introduced was fresh fruit (170 days from birth, median). Overall, infants shared a very similar diet, which was different from the family diet and characterized by delayed introduction of certain food types. Five percent of parents complied with either all five or only one of the WHO recommendations, 34% with three, and 35% with four. The parents' partial compliance with WHO recommendations is probably due to conflicting information received from different sources. This advocates for national evidence-based guidelines, supported and promoted by health professionals.

VL - 9 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28054972?dopt=Abstract ER - TY - JOUR T1 - ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development. JF - Sci Rep Y1 - 2017 A1 - Zhang, Rong A1 - Knapp, Michael A1 - Suzuki, Kentaro A1 - Kajioka, Daiki A1 - Schmidt, Johanna M A1 - Winkler, Jonas A1 - Yilmaz, Öznur A1 - Pleschka, Michael A1 - Cao, Jia A1 - Kockum, Christina Clementson A1 - Barker, Gillian A1 - Holmdahl, Gundela A1 - Beaman, Glenda A1 - Keene, David A1 - Woolf, Adrian S A1 - Cervellione, Raimondo M A1 - Cheng, Wei A1 - Wilkins, Simon A1 - Gearhart, John P A1 - Sirchia, Fabio A1 - Di Grazia, Massimo A1 - Ebert, Anne-Karolin A1 - Rösch, Wolfgang A1 - Ellinger, Jörg A1 - Jenetzky, Ekkehart A1 - Zwink, Nadine A1 - Feitz, Wout F A1 - Marcelis, Carlo A1 - Schumacher, Johannes A1 - Martinón-Torres, Federico A1 - Hibberd, Martin Lloyd A1 - Khor, Chiea Chuen A1 - Heilmann-Heimbach, Stefanie A1 - Barth, Sandra A1 - Boyadjiev, Simeon A A1 - Brusco, Alfredo A1 - Ludwig, Michael A1 - Newman, William A1 - Nordenskjöld, Agneta A1 - Yamada, Gen A1 - Odermatt, Benjamin A1 - Reutter, Heiko KW - Animals KW - Bladder Exstrophy KW - Embryo, Mammalian KW - Female KW - Gene Expression Regulation, Developmental KW - Genetic Predisposition to Disease KW - Humans KW - Larva KW - LIM-Homeodomain Proteins KW - Mesoderm KW - Mice KW - Organogenesis KW - Polymorphism, Single Nucleotide KW - Pronephros KW - Protein Isoforms KW - Transcription Factors KW - Urinary Tract KW - Zebrafish AB -

Previously genome-wide association methods in patients with classic bladder exstrophy (CBE) found association with ISL1, a master control gene expressed in pericloacal mesenchyme. This study sought to further explore the genetics in a larger set of patients following-up on the most promising genomic regions previously reported. Genotypes of 12 markers obtained from 268 CBE patients of Australian, British, German Italian, Spanish and Swedish origin and 1,354 ethnically matched controls and from 92 CBE case-parent trios from North America were analysed. Only marker rs6874700 at the ISL1 locus showed association (p = 2.22 × 10). A meta-analysis of rs6874700 of our previous and present study showed a p value of 9.2 × 10. Developmental biology models were used to clarify the location of ISL1 activity in the forming urinary tract. Genetic lineage analysis of Isl1-expressing cells by the lineage tracer mouse model showed Isl1-expressing cells in the urinary tract of mouse embryos at E10.5 and distributed in the bladder at E15.5. Expression of isl1 in zebrafish larvae staged 48 hpf was detected in a small region of the developing pronephros. Our study supports ISL1 as a major susceptibility gene for CBE and as a regulator of urinary tract development.

VL - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28176844?dopt=Abstract ER - TY - JOUR T1 - Multicentric Case-Control Study on Azathioprine Dose and Pharmacokinetics in Early-onset Pediatric Inflammatory Bowel Disease. JF - Inflamm Bowel Dis Y1 - 2017 A1 - Stocco, Gabriele A1 - Martelossi, Stefano A1 - Arrigo, Serena A1 - Barabino, Arrigo A1 - Aloi, Marina A1 - Martinelli, Massimo A1 - Miele, Erasmo A1 - Knafelz, Daniela A1 - Romano, Claudio A1 - Naviglio, Samuele A1 - Favretto, Diego A1 - Cuzzoni, Eva A1 - Franca, Raffaella A1 - Decorti, Giuliana A1 - Ventura, Alessandro KW - Adolescent KW - Age of Onset KW - Antimetabolites KW - Azathioprine KW - Case-Control Studies KW - Child KW - Child, Preschool KW - Chromatography, High Pressure Liquid KW - Dose-Response Relationship, Drug KW - Erythrocytes KW - Female KW - Guanine Nucleotides KW - Humans KW - Inflammatory Bowel Diseases KW - Male KW - Mercaptopurine KW - Methyltransferases KW - Thioguanine AB -

BACKGROUND: Early-onset inflammatory bowel disease (IBD) is generally aggressive, with a high probability of complications and need of surgery. Despite the introduction of highly effective biological drugs, treatment with azathioprine continues to be important even for early-onset IBD; however, in these patients azathioprine response seems to be reduced. This study evaluated azathioprine doses, metabolite concentrations, and their associations with patients' age in children with IBD treated at 6 tertiary pediatric referral centers.

METHODS: Azathioprine doses, metabolites, and clinical effects were assessed after at least 3 months of therapy in 17 early-onset (age < 6 yr, cases) and 51 nonearly-onset (aged > 12 and <18 yrs, controls) patients with IBD. Azathioprine dose was titrated on therapeutic efficacy (response and adverse effects). Azathioprine metabolites and thiopurine methyltransferase activity were determined by high-performance liquid chromatography with ultra violet-vis detection (HPLC-UV) methods.

RESULTS: Frequency of patients in remission was similar among early-onset and control groups, respectively (82% and 84%, P value = 0.72). Early-onset patients required higher doses of azathioprine (median 2.7 versus 2.0 mg·kg·d, P value = 1.1 × 10). Different doses resulted in comparable azathioprine active thioguanine nucleotide metabolite concentrations (median 263 versus 366 pmol/8 × 10 erythrocytes, P value = 0.41) and methylmercaptopurine nucleotide concentrations (median 1455 versus 1532 pmol/8 × 10 erythrocytes, P value = 0.60). Lower ratios between thioguanine nucleotide metabolites and azathioprine doses were found in early-onset patients (median 98 versus 184 pmol/8 × 10 erythrocytes·mg·kg·d, P value = 0.017). Interestingly, early-onset patients presented also higher thiopurine methyltransferase activity (median 476 versus 350 nmol methylmercaptopurine/mg hemoglobin/h, P-value = 0.046).

CONCLUSIONS: This study demonstrated that patients with early-onset IBD present increased inactivating azathioprine metabolism, likely because of elevated activity of the enzyme thiopurine methyltransferase.

VL - 23 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28296824?dopt=Abstract ER - TY - JOUR T1 - Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney. JF - Hypertension Y1 - 2017 A1 - Wain, Louise V A1 - Vaez, Ahmad A1 - Jansen, Rick A1 - Joehanes, Roby A1 - van der Most, Peter J A1 - Erzurumluoglu, A Mesut A1 - O'Reilly, Paul F A1 - Cabrera, Claudia P A1 - Warren, Helen R A1 - Rose, Lynda M A1 - Verwoert, Germaine C A1 - Hottenga, Jouke-Jan A1 - Strawbridge, Rona J A1 - Esko, Tõnu A1 - Arking, Dan E A1 - Hwang, Shih-Jen A1 - Guo, Xiuqing A1 - Kutalik, Zoltán A1 - Trompet, Stella A1 - Shrine, Nick A1 - Teumer, Alexander A1 - Ried, Janina S A1 - Bis, Joshua C A1 - Smith, Albert V A1 - Amin, Najaf A1 - Nolte, Ilja M A1 - Lyytikäinen, Leo-Pekka A1 - Mahajan, Anubha A1 - Wareham, Nicholas J A1 - Hofer, Edith A1 - Joshi, Peter K A1 - Kristiansson, Kati A1 - Traglia, Michela A1 - Havulinna, Aki S A1 - Goel, Anuj A1 - Nalls, Mike A A1 - Sõber, Siim A1 - Vuckovic, Dragana A1 - Luan, Jian'an A1 - del Greco M, Fabiola A1 - Ayers, Kristin L A1 - Marrugat, Jaume A1 - Ruggiero, Daniela A1 - Lopez, Lorna M A1 - Niiranen, Teemu A1 - Enroth, Stefan A1 - Jackson, Anne U A1 - Nelson, Christopher P A1 - Huffman, Jennifer E A1 - Zhang, Weihua A1 - Marten, Jonathan A1 - Gandin, Ilaria A1 - Harris, Sarah E A1 - Zemunik, Tatijana A1 - Lu, Yingchang A1 - Evangelou, Evangelos A1 - Shah, Nabi A1 - de Borst, Martin H A1 - Mangino, Massimo A1 - Prins, Bram P A1 - Campbell, Archie A1 - Li-Gao, Ruifang A1 - Chauhan, Ganesh A1 - Oldmeadow, Christopher A1 - Abecasis, Goncalo A1 - Abedi, Maryam A1 - Barbieri, Caterina M A1 - Barnes, Michael R A1 - Batini, Chiara A1 - Beilby, John A1 - Blake, Tineka A1 - Boehnke, Michael A1 - Bottinger, Erwin P A1 - Braund, Peter S A1 - Brown, Morris A1 - Brumat, Marco A1 - Campbell, Harry A1 - Chambers, John C A1 - Cocca, Massimiliano A1 - Collins, Francis A1 - Connell, John A1 - Cordell, Heather J A1 - Damman, Jeffrey J A1 - Davies, Gail A1 - de Geus, Eco J A1 - de Mutsert, Renée A1 - Deelen, Joris A1 - Demirkale, Yusuf A1 - Doney, Alex S F A1 - Dörr, Marcus A1 - Farrall, Martin A1 - Ferreira, Teresa A1 - Frånberg, Mattias A1 - Gao, He A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Giulianini, Franco A1 - Gow, Alan J A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hofman, Albert A1 - Holliday, Elizabeth G A1 - Hui, Jennie A1 - Järvelin, Marjo-Riitta A1 - Johansson, Åsa A1 - Johnson, Andrew D A1 - Jousilahti, Pekka A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kathiresan, Sekar A1 - Khaw, Kay-Tee A1 - Kolcic, Ivana A1 - Koskinen, Seppo A1 - Langenberg, Claudia A1 - Larson, Marty A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Liewald, David C M A1 - Lin, Li A1 - Lind, Lars A1 - Mach, François A1 - Mamasoula, Chrysovalanto A1 - Menni, Cristina A1 - Mifsud, Borbala A1 - Milaneschi, Yuri A1 - Morgan, Anna A1 - Morris, Andrew D A1 - Morrison, Alanna C A1 - Munson, Peter J A1 - Nandakumar, Priyanka A1 - Nguyen, Quang Tri A1 - Nutile, Teresa A1 - Oldehinkel, Albertine J A1 - Oostra, Ben A A1 - Org, Elin A1 - Padmanabhan, Sandosh A1 - Palotie, Aarno A1 - Paré, Guillaume A1 - Pattie, Alison A1 - Penninx, Brenda W J H A1 - Poulter, Neil A1 - Pramstaller, Peter P A1 - Raitakari, Olli T A1 - Ren, Meixia A1 - Rice, Kenneth A1 - Ridker, Paul M A1 - Riese, Harriëtte A1 - Ripatti, Samuli A1 - Robino, Antonietta A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Saba, Yasaman A1 - Saint Pierre, Aude A1 - Sala, Cinzia F A1 - Sarin, Antti-Pekka A1 - Schmidt, Reinhold A1 - Scott, Rodney A1 - Seelen, Marc A A1 - Shields, Denis C A1 - Siscovick, David A1 - Sorice, Rossella A1 - Stanton, Alice A1 - Stott, David J A1 - Sundström, Johan A1 - Swertz, Morris A1 - Taylor, Kent D A1 - Thom, Simon A1 - Tzoulaki, Ioanna A1 - Tzourio, Christophe A1 - Uitterlinden, André G A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Wild, Sarah A1 - Willemsen, Gonneke A1 - Wright, Alan F A1 - Yao, Jie A1 - Thériault, Sébastien A1 - Conen, David A1 - Attia, John A1 - Sever, Peter A1 - Debette, Stéphanie A1 - Mook-Kanamori, Dennis O A1 - Zeggini, Eleftheria A1 - Spector, Tim D A1 - van der Harst, Pim A1 - Palmer, Colin N A A1 - Vergnaud, Anne-Claire A1 - Loos, Ruth J F A1 - Polasek, Ozren A1 - Starr, John M A1 - Girotto, Giorgia A1 - Hayward, Caroline A1 - Kooner, Jaspal S A1 - Lindgren, Cecila M A1 - Vitart, Veronique A1 - Samani, Nilesh J A1 - Tuomilehto, Jaakko A1 - Gyllensten, Ulf A1 - Knekt, Paul A1 - Deary, Ian J A1 - Ciullo, Marina A1 - Elosua, Roberto A1 - Keavney, Bernard D A1 - Hicks, Andrew A A1 - Scott, Robert A A1 - Gasparini, Paolo A1 - Laan, Maris A1 - Liu, Yongmei A1 - Watkins, Hugh A1 - Hartman, Catharina A A1 - Salomaa, Veikko A1 - Toniolo, Daniela A1 - Perola, Markus A1 - Wilson, James F A1 - Schmidt, Helena A1 - Zhao, Jing Hua A1 - Lehtimäki, Terho A1 - van Duijn, Cornelia M A1 - Gudnason, Vilmundur A1 - Psaty, Bruce M A1 - Peters, Annette A1 - Rettig, Rainer A1 - James, Alan A1 - Jukema, J Wouter A1 - Strachan, David P A1 - Palmas, Walter A1 - Metspalu, Andres A1 - Ingelsson, Erik A1 - Boomsma, Dorret I A1 - Franco, Oscar H A1 - Bochud, Murielle A1 - Newton-Cheh, Christopher A1 - Munroe, Patricia B A1 - Elliott, Paul A1 - Chasman, Daniel I A1 - Chakravarti, Aravinda A1 - Knight, Joanne A1 - Morris, Andrew P A1 - Levy, Daniel A1 - Tobin, Martin D A1 - Snieder, Harold A1 - Caulfield, Mark J A1 - Ehret, Georg B AB -

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near , , , , , and , and provide new replication evidence for a further 2 signals in and Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/28739976?dopt=Abstract ER - TY - JOUR T1 - Rare and low-frequency coding variants alter human adult height. JF - Nature Y1 - 2017 A1 - Marouli, Eirini A1 - Graff, Mariaelisa A1 - Medina-Gomez, Carolina A1 - Lo, Ken Sin A1 - Wood, Andrew R A1 - Kjaer, Troels R A1 - Fine, Rebecca S A1 - Lu, Yingchang A1 - Schurmann, Claudia A1 - Highland, Heather M A1 - Rüeger, Sina A1 - Thorleifsson, Gudmar A1 - Justice, Anne E A1 - Lamparter, David A1 - Stirrups, Kathleen E A1 - Turcot, Valérie A1 - Young, Kristin L A1 - Winkler, Thomas W A1 - Esko, Tõnu A1 - Karaderi, Tugce A1 - Locke, Adam E A1 - Masca, Nicholas G D A1 - Ng, Maggie C Y A1 - Mudgal, Poorva A1 - Rivas, Manuel A A1 - Vedantam, Sailaja A1 - Mahajan, Anubha A1 - Guo, Xiuqing A1 - Abecasis, Goncalo A1 - Aben, Katja K A1 - Adair, Linda S A1 - Alam, Dewan S A1 - Albrecht, Eva A1 - Allin, Kristine H A1 - Allison, Matthew A1 - Amouyel, Philippe A1 - Appel, Emil V A1 - Arveiler, Dominique A1 - Asselbergs, Folkert W A1 - Auer, Paul L A1 - Balkau, Beverley A1 - Banas, Bernhard A1 - Bang, Lia E A1 - Benn, Marianne A1 - Bergmann, Sven A1 - Bielak, Lawrence F A1 - Blüher, Matthias A1 - Boeing, Heiner A1 - Boerwinkle, Eric A1 - Böger, Carsten A A1 - Bonnycastle, Lori L A1 - Bork-Jensen, Jette A1 - Bots, Michiel L A1 - Bottinger, Erwin P A1 - Bowden, Donald W A1 - Brandslund, Ivan A1 - Breen, Gerome A1 - Brilliant, Murray H A1 - Broer, Linda A1 - Burt, Amber A A1 - Butterworth, Adam S A1 - Carey, David J A1 - Caulfield, Mark J A1 - Chambers, John C A1 - Chasman, Daniel I A1 - Chen, Yii-Der Ida A1 - Chowdhury, Rajiv A1 - Christensen, Cramer A1 - Chu, Audrey Y A1 - Cocca, Massimiliano A1 - Collins, Francis S A1 - Cook, James P A1 - Corley, Janie A1 - Galbany, Jordi Corominas A1 - Cox, Amanda J A1 - Cuellar-Partida, Gabriel A1 - Danesh, John A1 - Davies, Gail A1 - de Bakker, Paul I W A1 - de Borst, Gert J A1 - de Denus, Simon A1 - de Groot, Mark C H A1 - de Mutsert, Renée A1 - Deary, Ian J A1 - Dedoussis, George A1 - Demerath, Ellen W A1 - den Hollander, Anneke I A1 - Dennis, Joe G A1 - Di Angelantonio, Emanuele A1 - Drenos, Fotios A1 - Du, Mengmeng A1 - Dunning, Alison M A1 - Easton, Douglas F A1 - Ebeling, Tapani A1 - Edwards, Todd L A1 - Ellinor, Patrick T A1 - Elliott, Paul A1 - Evangelou, Evangelos A1 - Farmaki, Aliki-Eleni A1 - Faul, Jessica D A1 - Feitosa, Mary F A1 - Feng, Shuang A1 - Ferrannini, Ele A1 - Ferrario, Marco M A1 - Ferrières, Jean A1 - Florez, Jose C A1 - Ford, Ian A1 - Fornage, Myriam A1 - Franks, Paul W A1 - Frikke-Schmidt, Ruth A1 - Galesloot, Tessel E A1 - Gan, Wei A1 - Gandin, Ilaria A1 - Gasparini, Paolo A1 - Giedraitis, Vilmantas A1 - Giri, Ayush A1 - Girotto, Giorgia A1 - Gordon, Scott D A1 - Gordon-Larsen, Penny A1 - Gorski, Mathias A1 - Grarup, Niels A1 - Grove, Megan L A1 - Gudnason, Vilmundur A1 - Gustafsson, Stefan A1 - Hansen, Torben A1 - Harris, Kathleen Mullan A1 - Harris, Tamara B A1 - Hattersley, Andrew T A1 - Hayward, Caroline A1 - He, Liang A1 - Heid, Iris M A1 - Heikkilä, Kauko A1 - Helgeland, Øyvind A1 - Hernesniemi, Jussi A1 - Hewitt, Alex W A1 - Hocking, Lynne J A1 - Hollensted, Mette A1 - Holmen, Oddgeir L A1 - Hovingh, G Kees A1 - Howson, Joanna M M A1 - Hoyng, Carel B A1 - Huang, Paul L A1 - Hveem, Kristian A1 - Ikram, M Arfan A1 - Ingelsson, Erik A1 - Jackson, Anne U A1 - Jansson, Jan-Håkan A1 - Jarvik, Gail P A1 - Jensen, Gorm B A1 - Jhun, Min A A1 - Jia, Yucheng A1 - Jiang, Xuejuan A1 - Johansson, Stefan A1 - Jørgensen, Marit E A1 - Jørgensen, Torben A1 - Jousilahti, Pekka A1 - Jukema, J Wouter A1 - Kahali, Bratati A1 - Kahn, René S A1 - Kähönen, Mika A1 - Kamstrup, Pia R A1 - Kanoni, Stavroula A1 - Kaprio, Jaakko A1 - Karaleftheri, Maria A1 - Kardia, Sharon L R A1 - Karpe, Fredrik A1 - Kee, Frank A1 - Keeman, Renske A1 - Kiemeney, Lambertus A A1 - Kitajima, Hidetoshi A1 - Kluivers, Kirsten B A1 - Kocher, Thomas A1 - Komulainen, Pirjo A1 - Kontto, Jukka A1 - Kooner, Jaspal S A1 - Kooperberg, Charles A1 - Kovacs, Peter A1 - Kriebel, Jennifer A1 - Kuivaniemi, Helena A1 - Küry, Sébastien A1 - Kuusisto, Johanna A1 - La Bianca, Martina A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lange, Ethan M A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Larson, Eric B A1 - Lee, I-Te A1 - Lehtimäki, Terho A1 - Lewis, Cora E A1 - Li, Huaixing A1 - Li, Jin A1 - Li-Gao, Ruifang A1 - Lin, Honghuang A1 - Lin, Li-An A1 - Lin, Xu A1 - Lind, Lars A1 - Lindström, Jaana A1 - Linneberg, Allan A1 - Liu, Yeheng A1 - Liu, Yongmei A1 - Lophatananon, Artitaya A1 - Luan, Jian'an A1 - Lubitz, Steven A A1 - Lyytikäinen, Leo-Pekka A1 - Mackey, David A A1 - Madden, Pamela A F A1 - Manning, Alisa K A1 - Männistö, Satu A1 - Marenne, Gaëlle A1 - Marten, Jonathan A1 - Martin, Nicholas G A1 - Mazul, Angela L A1 - Meidtner, Karina A1 - Metspalu, Andres A1 - Mitchell, Paul A1 - Mohlke, Karen L A1 - Mook-Kanamori, Dennis O A1 - Morgan, Anna A1 - Morris, Andrew D A1 - Morris, Andrew P A1 - Müller-Nurasyid, Martina A1 - Munroe, Patricia B A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nelson, Christopher P A1 - Neville, Matt A1 - Nielsen, Sune F A1 - Nikus, Kjell A1 - Njølstad, Pål R A1 - Nordestgaard, Børge G A1 - Ntalla, Ioanna A1 - O'Connel, Jeffrey R A1 - Oksa, Heikki A1 - Loohuis, Loes M Olde A1 - Ophoff, Roel A A1 - Owen, Katharine R A1 - Packard, Chris J A1 - Padmanabhan, Sandosh A1 - Palmer, Colin N A A1 - Pasterkamp, Gerard A1 - Patel, Aniruddh P A1 - Pattie, Alison A1 - Pedersen, Oluf A1 - Peissig, Peggy L A1 - Peloso, Gina M A1 - Pennell, Craig E A1 - Perola, Markus A1 - Perry, James A A1 - Perry, John R B A1 - Person, Thomas N A1 - Pirie, Ailith A1 - Polasek, Ozren A1 - Posthuma, Danielle A1 - Raitakari, Olli T A1 - Rasheed, Asif A1 - Rauramaa, Rainer A1 - Reilly, Dermot F A1 - Reiner, Alex P A1 - Renstrom, Frida A1 - Ridker, Paul M A1 - Rioux, John D A1 - Robertson, Neil A1 - Robino, Antonietta A1 - Rolandsson, Olov A1 - Rudan, Igor A1 - Ruth, Katherine S A1 - Saleheen, Danish A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Sandow, Kevin A1 - Sapkota, Yadav A1 - Sattar, Naveed A1 - Schmidt, Marjanka K A1 - Schreiner, Pamela J A1 - Schulze, Matthias B A1 - Scott, Robert A A1 - Segura-Lepe, Marcelo P A1 - Shah, Svati A1 - Sim, Xueling A1 - Sivapalaratnam, Suthesh A1 - Small, Kerrin S A1 - Smith, Albert Vernon A1 - Smith, Jennifer A A1 - Southam, Lorraine A1 - Spector, Timothy D A1 - Speliotes, Elizabeth K A1 - Starr, John M A1 - Steinthorsdottir, Valgerdur A1 - Stringham, Heather M A1 - Stumvoll, Michael A1 - Surendran, Praveen A1 - 't Hart, Leen M A1 - Tansey, Katherine E A1 - Tardif, Jean-Claude A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Thompson, Deborah J A1 - Thorsteinsdottir, Unnur A1 - Thuesen, Betina H A1 - Tönjes, Anke A1 - Tromp, Gerard A1 - Trompet, Stella A1 - Tsafantakis, Emmanouil A1 - Tuomilehto, Jaakko A1 - Tybjaerg-Hansen, Anne A1 - Tyrer, Jonathan P A1 - Uher, Rudolf A1 - Uitterlinden, André G A1 - Ulivi, Sheila A1 - van der Laan, Sander W A1 - Van Der Leij, Andries R A1 - van Duijn, Cornelia M A1 - van Schoor, Natasja M A1 - van Setten, Jessica A1 - Varbo, Anette A1 - Varga, Tibor V A1 - Varma, Rohit A1 - Edwards, Digna R Velez A1 - Vermeulen, Sita H A1 - Vestergaard, Henrik A1 - Vitart, Veronique A1 - Vogt, Thomas F A1 - Vozzi, Diego A1 - Walker, Mark A1 - Wang, Feijie A1 - Wang, Carol A A1 - Wang, Shuai A1 - Wang, Yiqin A1 - Wareham, Nicholas J A1 - Warren, Helen R A1 - Wessel, Jennifer A1 - Willems, Sara M A1 - Wilson, James G A1 - Witte, Daniel R A1 - Woods, Michael O A1 - Wu, Ying A1 - Yaghootkar, Hanieh A1 - Yao, Jie A1 - Yao, Pang A1 - Yerges-Armstrong, Laura M A1 - Young, Robin A1 - Zeggini, Eleftheria A1 - Zhan, Xiaowei A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Zhao, Wei A1 - Zhao, Wei A1 - Zheng, He A1 - Zhou, Wei A1 - Rotter, Jerome I A1 - Boehnke, Michael A1 - Kathiresan, Sekar A1 - McCarthy, Mark I A1 - Willer, Cristen J A1 - Stefansson, Kari A1 - Borecki, Ingrid B A1 - Liu, Dajiang J A1 - North, Kari E A1 - Heard-Costa, Nancy L A1 - Pers, Tune H A1 - Lindgren, Cecilia M A1 - Oxvig, Claus A1 - Kutalik, Zoltán A1 - Rivadeneira, Fernando A1 - Loos, Ruth J F A1 - Frayling, Timothy M A1 - Hirschhorn, Joel N A1 - Deloukas, Panos A1 - Lettre, Guillaume KW - ADAMTS Proteins KW - Adult KW - Alleles KW - Body Height KW - Cell Adhesion Molecules KW - Female KW - Gene Frequency KW - Genetic Variation KW - Genome, Human KW - Glycoproteins KW - Glycosaminoglycans KW - Hedgehog Proteins KW - Humans KW - Intercellular Signaling Peptides and Proteins KW - Interferon Regulatory Factors KW - Interleukin-11 Receptor alpha Subunit KW - Male KW - Multifactorial Inheritance KW - NADPH Oxidase 4 KW - NADPH Oxidases KW - Phenotype KW - Pregnancy-Associated Plasma Protein-A KW - Procollagen N-Endopeptidase KW - Proteoglycans KW - Proteolysis KW - Receptors, Androgen KW - Somatomedins AB -

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

VL - 542 IS - 7640 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28146470?dopt=Abstract ER - TY - JOUR T1 - Targeted sequencing identifies novel variants involved in autosomal recessive hereditary hearing loss in Qatari families. JF - Mutat Res Y1 - 2017 A1 - Alkowari, Moza K A1 - Vozzi, Diego A1 - Bhagat, Shruti A1 - Krishnamoorthy, Navaneethakrishnan A1 - Morgan, Anna A1 - Hayder, Yousra A1 - Logendra, Barathy A1 - Najjar, Nehal A1 - Gandin, Ilaria A1 - Gasparini, Paolo A1 - Badii, Ramin A1 - Girotto, Giorgia A1 - Abdulhadi, Khalid KW - Adolescent KW - Alleles KW - Cadherins KW - Child KW - Child, Preschool KW - Connexins KW - Female KW - GPI-Linked Proteins KW - Hearing Loss, Sensorineural KW - Humans KW - Infant KW - Male KW - Membrane Proteins KW - Models, Molecular KW - Mutation KW - Myosin Heavy Chains KW - Pedigree KW - Protein Conformation KW - Qatar KW - Sequence Analysis, DNA AB -

Hereditary hearing loss is characterized by a very high genetic heterogeneity. In the Qatari population the role of GJB2, the worldwide HHL major player, seems to be quite limited compared to Caucasian populations. In this study we analysed 18 Qatari families affected by non-syndromic hearing loss using a targeted sequencing approach that allowed us to analyse 81 genes simultaneously. Thanks to this approach, 50% of these families (9 out of 18) resulted positive for the presence of likely causative alleles in 6 different genes: CDH23, MYO6, GJB6, OTOF, TMC1 and OTOA. In particular, 4 novel alleles were detected while the remaining ones were already described to be associated to HHL in other ethnic groups. Molecular modelling has been used to further investigate the role of novel alleles identified in CDH23 and TMC1 genes demonstrating their crucial role in Ca2+ binding and therefore possible functional role in proteins. Present study showed that an accurate molecular diagnosis based on next generation sequencing technologies might largely improve molecular diagnostics outcome leading to benefits for both genetic counseling and definition of recurrence risk.

VL - 800-802 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28501645?dopt=Abstract ER - TY - JOUR T1 - Whole-body MRI reveals high incidence of osteonecrosis in children treated for Hodgkin lymphoma. JF - Br J Haematol Y1 - 2017 A1 - Littooij, Annemieke S A1 - Kwee, Thomas C A1 - Enríquez, Goya A1 - Verbeke, Jonathan I M L A1 - Granata, Claudio A1 - Beishuizen, Auke A1 - de Lange, Charlotte A1 - Zennaro, Floriana A1 - Bruin, Marrie C A A1 - Nievelstein, Rutger A J KW - Adolescent KW - Antineoplastic Combined Chemotherapy Protocols KW - Child KW - Doxorubicin KW - Epiphyses KW - Etoposide KW - Female KW - Hodgkin Disease KW - Humans KW - Incidence KW - Magnetic Resonance Imaging KW - Male KW - Osteonecrosis KW - Prednisone KW - Prospective Studies KW - Vincristine AB -

Osteonecrosis is a well-recognized complication in patients treated with corticosteroids. The incidence of osteonecrosis in children treated for Hodgkin lymphoma is unknown because prospective whole-body magnetic resonance imaging (MRI) studies are lacking in this patient population. Paediatric patients with newly diagnosed Hodgkin lymphoma who were treated according to a uniform paediatric Hodgkin protocol were eligible for inclusion in this prospective study. Whole-body MRI was performed in all 24 included patients (mean age 15·1 years, 12 girls) both before treatment and after 2 cycles of chemotherapy, and in 16 patients after completion of chemotherapy. Osteonecrosis was identified in 10 patients (41·7%, 95% confidence interval: 22·0-61·4%), with a total of 56 osteonecrotic sites. Osteonecrosis was detected in 8 patients after 2 cycles of OEPA (vincristine, etoposide, prednisone, doxorubicin), and in 2 additional patients after completion of chemotherapy. Epiphyseal involvement of long bones was seen in 4 of 10 children. None of the patients with osteonecrosis had any signs of bone collapse at the times of scanning. Whole-body MRI demonstrates osteonecrosis to be a common finding occurring during therapy response assessment of paediatric Hodgkin lymphoma. Detection of early epiphyseal osteonecrosis could allow for treatment before bone collapse and joint damage may occur.

VL - 176 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27891588?dopt=Abstract ER - TY - JOUR T1 - Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits. JF - Am J Hum Genet Y1 - 2017 A1 - Tachmazidou, Ioanna A1 - Süveges, Dániel A1 - Min, Josine L A1 - Ritchie, Graham R S A1 - Steinberg, Julia A1 - Walter, Klaudia A1 - Iotchkova, Valentina A1 - Schwartzentruber, Jeremy A1 - Huang, Jie A1 - Memari, Yasin A1 - McCarthy, Shane A1 - Crawford, Andrew A A1 - Bombieri, Cristina A1 - Cocca, Massimiliano A1 - Farmaki, Aliki-Eleni A1 - Gaunt, Tom R A1 - Jousilahti, Pekka A1 - Kooijman, Marjolein N A1 - Lehne, Benjamin A1 - Malerba, Giovanni A1 - Männistö, Satu A1 - Matchan, Angela A1 - Medina-Gomez, Carolina A1 - Metrustry, Sarah J A1 - Nag, Abhishek A1 - Ntalla, Ioanna A1 - Paternoster, Lavinia A1 - Rayner, Nigel W A1 - Sala, Cinzia A1 - Scott, William R A1 - Shihab, Hashem A A1 - Southam, Lorraine A1 - St Pourcain, Beate A1 - Traglia, Michela A1 - Trajanoska, Katerina A1 - Zaza, Gialuigi A1 - Zhang, Weihua A1 - Artigas, María S A1 - Bansal, Narinder A1 - Benn, Marianne A1 - Chen, Zhongsheng A1 - Danecek, Petr A1 - Lin, Wei-Yu A1 - Locke, Adam A1 - Luan, Jian'an A1 - Manning, Alisa K A1 - Mulas, Antonella A1 - Sidore, Carlo A1 - Tybjaerg-Hansen, Anne A1 - Varbo, Anette A1 - Zoledziewska, Magdalena A1 - Finan, Chris A1 - Hatzikotoulas, Konstantinos A1 - Hendricks, Audrey E A1 - Kemp, John P A1 - Moayyeri, Alireza A1 - Panoutsopoulou, Kalliope A1 - Szpak, Michal A1 - Wilson, Scott G A1 - Boehnke, Michael A1 - Cucca, Francesco A1 - Di Angelantonio, Emanuele A1 - Langenberg, Claudia A1 - Lindgren, Cecilia A1 - McCarthy, Mark I A1 - Morris, Andrew P A1 - Nordestgaard, Børge G A1 - Scott, Robert A A1 - Tobin, Martin D A1 - Wareham, Nicholas J A1 - Burton, Paul A1 - Chambers, John C A1 - Smith, George Davey A1 - Dedoussis, George A1 - Felix, Janine F A1 - Franco, Oscar H A1 - Gambaro, Giovanni A1 - Gasparini, Paolo A1 - Hammond, Christopher J A1 - Hofman, Albert A1 - Jaddoe, Vincent W V A1 - Kleber, Marcus A1 - Kooner, Jaspal S A1 - Perola, Markus A1 - Relton, Caroline A1 - Ring, Susan M A1 - Rivadeneira, Fernando A1 - Salomaa, Veikko A1 - Spector, Timothy D A1 - Stegle, Oliver A1 - Toniolo, Daniela A1 - Uitterlinden, André G A1 - Barroso, Inês A1 - Greenwood, Celia M T A1 - Perry, John R B A1 - Walker, Brian R A1 - Butterworth, Adam S A1 - Xue, Yali A1 - Durbin, Richard A1 - Small, Kerrin S A1 - Soranzo, Nicole A1 - Timpson, Nicholas J A1 - Zeggini, Eleftheria KW - Anthropometry KW - Body Height KW - Cohort Studies KW - Databases, Genetic KW - DNA Methylation KW - Female KW - Genetic Variation KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Lipodystrophy KW - Male KW - Meta-Analysis as Topic KW - Obesity KW - Physical Chromosome Mapping KW - Quantitative Trait Loci KW - Sequence Analysis, DNA KW - Sex Characteristics KW - Syndrome KW - United Kingdom AB -

Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.

VL - 100 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28552196?dopt=Abstract ER - TY - JOUR T1 - Clinical and pathogenetic features of ETV6 related thrombocytopenia with predisposition to acute lymphoblastic leukemia. JF - Haematologica Y1 - 2016 A1 - Melazzini, Federica A1 - Palombo, Flavia A1 - Balduini, Alessandra A1 - De Rocco, Daniela A1 - Marconi, Caterina A1 - Noris, Patrizia A1 - Gnan, Chiara A1 - Pippucci, Tommaso A1 - Bozzi, Valeria A1 - Faleschini, Michela A1 - Barozzi, Serena A1 - Doubek, Michael A1 - Di Buduo, Christian A A1 - Stano Kozubik, Katerina A1 - Radova, Lenka A1 - Loffredo, Giuseppe A1 - Pospisilova, Sarka A1 - Alfano, Caterina A1 - Seri, Marco A1 - Balduini, Carlo L A1 - Pecci, Alessandro A1 - Savoia, Anna AB -

ETV6-related thrombocytopenia (ETV6-RT) is an autosomal dominant thrombocytopenia that has been recently identified in a few families and has been suspected to predispose to hematological malignancies. To gain further information on this disorder, we searched for ETV6 mutations in the 130 families with inherited thrombocytopenia of unknown origin from our cohort of 274 consecutive pedigrees with familial thrombocytopenia. We identified 20 ETV6-RT patients from 7 pedigrees. They have 5 different ETV6 variants, including three novel mutations affecting the highly conserved E26 transformation-specific domain. The relative frequency of ETV6-RT resulted 2.6% in the whole case series and 4.6% among the families with known forms of inherited thrombocytopenia. The degree of thrombocytopenia and bleeding tendency of ETV6-RT patients were mild, but 4 subjects developed B-cell acute lymphoblastic leukemia during childhood, resulting in a significantly increased incidence compared to the general population. Clinical and laboratory findings did not identify any peculiar defects that can be used to suspect this disorder by routine diagnostic workup. However, at variance with most inherited thrombocytopenias, platelet size was not enlarged. In vitro studies revealed that patients megakaryocytes have defective maturation and impaired proplatelet formation. Moreover, ETV6-RT platelets have reduced ability to spread on fibrinogen. Since also the dominant thrombocytopenias due to mutations in RUNX1 and ANKRD26 are characterized by normal platelet size and predispose to hematological malignancies, we suggest that mutation screening of ETV6, RUNX1 and ANKRD26 should be performed in all the subjects with autosomal dominant thrombocytopenia and normal platelet size.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/27365488?dopt=Abstract ER - TY - JOUR T1 - Current concepts in management of pain in children in the emergency department. JF - Lancet Y1 - 2016 A1 - Krauss, Baruch S A1 - Calligaris, Lorenzo A1 - Green, Steven M A1 - Barbi, Egidio KW - Acute Pain KW - Analgesics, Opioid KW - Anesthetics, Local KW - Anti-Inflammatory Agents, Non-Steroidal KW - Anxiety KW - Child KW - Emergency Medicine KW - Emergency Service, Hospital KW - Humans KW - Pain Management KW - Pediatrics KW - Stress, Psychological AB -

Pain is common in children presenting to emergency departments with episodic illnesses, acute injuries, and exacerbation of chronic disorders. We review recognition and assessment of pain in infants and children and discuss the manifestations of pain in children with chronic illness, recurrent pain syndromes, and cognitive impairment, including the difficulties of pain management in these patients. Non-pharmacological interventions, as adjuncts to pharmacological management for acute anxiety and pain, are described by age and development. We discuss the pharmacological management of acute pain and anxiety, reviewing invasive and non-invasive routes of administration, pharmacology, and adverse effects.

VL - 387 IS - 10013 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26095580?dopt=Abstract ER - TY - JOUR T1 - Detection of Malawi polyomavirus sequences in secondary lymphoid tissues from Italian healthy children: a transient site of infection. JF - Virol J Y1 - 2016 A1 - Papa, N A1 - Zanotta, N A1 - Knowles, A A1 - Orzan, E A1 - Comar, M AB -

BACKGROUND: The novel Malawi polyomavirus (MWPyV) was initially detected in stool specimens from healthy children and children with gastrointestinal symptoms, mostly diarrhea, indicating that MWPyV might play a role in human gastroenteric diseases. Recently, MWPyV sequences were additionally identified in respiratory secretions from both healthy and acutely ill children suggesting that MWPyV may have a tropism for different human tissues. This study was designed to investigate the possible sites of latency/persistence for MWPyV in a cohort of healthy Italian children.

METHODS: Specimens (n° 500) of tonsils, adenoids, blood, urines and feces, from 200 healthy and immunocompetent children (age range: 1-15 years) were tested for the amplification of the MWPyV LT antigen sequence by quantitative real-time PCR. Samples (n° 80) of blood and urines from 40 age-matched children with autoimmune diseases, were screened for comparison. Polyomaviruses JC/BK and Epstein-Barr Virus (EBV) were also tested as markers of infection in all samples using the same molecular technique.

RESULTS: In our series of healthy children, MWPyV was detected only in the lymphoid tissues showing a prevalence of 6 % in tonsils and 1 % in adenoids, although with a low viral load. No JCPyV or BKPyV co-infection was found in MWPyV positive samples, while EBV showed a similar percentage of both in tonsils and adenoids (38 and 37 %). Conversely, no MWPyV DNA was detected in stool from babies with gastroenteric syndrome. With regards to autoimmune children, neither MWPyV nor BKPyV were detected in blood, while JCPyV viremia was observed in 15 % (6/40) of children treated with Infliximab. Urinary BKPyV shedding was observed in 12.5 % (5/40) while JCPyV in 100 % of the samples.

CONCLUSIONS: The detection of MWPyV sequences in tonsils and adenoids of healthy children suggests that secondary lymphoid tissues can harbour MWPyV probably as transient sites of persistence rather than actual sites of latency.

VL - 13 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27287743?dopt=Abstract ER - TY - JOUR T1 - EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy. JF - Brain Y1 - 2016 A1 - Byrne, Susan A1 - Jansen, Lara A1 - U-King-Im, Jean-Marie A1 - Siddiqui, Ata A1 - Lidov, Hart G W A1 - Bodi, Istvan A1 - Smith, Luke A1 - Mein, Rachael A1 - Cullup, Thomas A1 - Dionisi-Vici, Carlo A1 - Al-Gazali, Lihadh A1 - Al-Owain, Mohammed A1 - Bruwer, Zandre A1 - Al Thihli, Khalid A1 - El-Garhy, Rana A1 - Flanigan, Kevin M A1 - Manickam, Kandamurugu A1 - Zmuda, Erik A1 - Banks, Wesley A1 - Gershoni-Baruch, Ruth A1 - Mandel, Hanna A1 - Dagan, Efrat A1 - Raas-Rothschild, Annick A1 - Barash, Hila A1 - Filloux, Francis A1 - Creel, Donnell A1 - Harris, Michael A1 - Hamosh, Ada A1 - Kölker, Stefan A1 - Ebrahimi-Fakhari, Darius A1 - Hoffmann, Georg F A1 - Manchester, David A1 - Boyer, Philip J A1 - Manzur, Adnan Y A1 - Lourenco, Charles Marques A1 - Pilz, Daniela T A1 - Kamath, Arveen A1 - Prabhakar, Prab A1 - Rao, Vamshi K A1 - Rogers, R Curtis A1 - Ryan, Monique M A1 - Brown, Natasha J A1 - McLean, Catriona A A1 - Said, Edith A1 - Schara, Ulrike A1 - Stein, Anja A1 - Sewry, Caroline A1 - Travan, Laura A1 - Wijburg, Frits A A1 - Zenker, Martin A1 - Mohammed, Shehla A1 - Fanto, Manolis A1 - Gautel, Mathias A1 - Jungbluth, Heinz KW - Agenesis of Corpus Callosum KW - Animals KW - Autophagy KW - Cataract KW - Child, Preschool KW - Cross-Sectional Studies KW - Drosophila melanogaster KW - Female KW - Hippocampus KW - Humans KW - Male KW - Mutation KW - Neurodevelopmental Disorders KW - Proteins KW - Retrospective Studies AB -

Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0-49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities. Nerve biopsy performed in one case revealed subtotal absence of myelinated axons. Post-mortem examinations in three patients confirmed neurodevelopmental and neurodegenerative features and multisystem involvement. Finally, downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration. We conclude that EPG5-related Vici syndrome defines a novel group of neurodevelopmental disorders that should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded. Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease.

VL - 139 IS - Pt 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26917586?dopt=Abstract ER - TY - JOUR T1 - Epigenetic Signals on Plant Adaptation: A Biotic Stress Perspective. JF - Curr Protein Pept Sci Y1 - 2016 A1 - Neto, José Ribamar Costa Ferreira A1 - da Silva, Manassés Daniel A1 - Pandolfi, Valesca A1 - Crovella, Sergio A1 - Benko-Iseppon, Ana Maria A1 - Kido, Éderson Akio AB -

For sessile organisms such as plants, regulatory mechanisms of gene expression are vital, since they remain exposed to climatic and biological threats. Thus, they have to face hazards with instantaneous reorganization of their internal environment. For this purpose, besides the use of transcription factors, the participation of chromatin as an active factor in the regulation of transcription is crucial. Chemical changes in chromatin structure affect the accessibility of the transcriptional machinery and acting in signaling, engaging/inhibiting factors that participate in the transcription processes. Mechanisms in which gene expression undergoes changes without the occurrence of DNA gene mutations in the monomers that make up DNA, are understood as epigenetic phenomena. These include (1) post-translational modifications of histones, which results in stimulation or repression of gene activity and (2) cytosine methylation in the promoter region of individual genes, both preventing access of transcriptional activators as well as signaling the recruitment of repressors. There is evidence that such modifications can pass on to subsequent generations of daughter cells and even generations of individuals. However, reports indicate that they persist only in the presence of a stressor factor (or an inductor of the above-mentioned modifications). In its absence, these modifications weaken or lose heritability, being eliminated in the next few generations. In this review, it is argued how epigenetic signals influence gene regulation, the mechanisms involved and their participation in processes of resistance to biotic stresses, controlling processes of the plant immune system.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/27455972?dopt=Abstract ER - TY - JOUR T1 - Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index. JF - Mol Psychiatry Y1 - 2016 A1 - Hinney, A A1 - Kesselmeier, M A1 - Jall, S A1 - Volckmar, A-L A1 - Föcker, M A1 - Antel, J A1 - Heid, I M A1 - Winkler, T W A1 - Grant, S F A A1 - Guo, Y A1 - Bergen, A W A1 - Kaye, W A1 - Berrettini, W A1 - Hakonarson, H A1 - Herpertz-Dahlmann, B A1 - de Zwaan, M A1 - Herzog, W A1 - Ehrlich, S A1 - Zipfel, S A1 - Egberts, K M A1 - Adan, R A1 - Brandys, M A1 - van Elburg, A A1 - Boraska Perica, V A1 - Franklin, C S A1 - Tschöp, M H A1 - Zeggini, E A1 - Bulik, C M A1 - Collier, D A1 - Scherag, A A1 - Müller, T D A1 - Hebebrand, J AB -

The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single-nucleotide polymorphisms (SNPs) with the lowest P-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI-related loci was performed in the AN GWAMA. We detected significant associations (P-values <5 × 10(-5), Bonferroni-corrected P<0.05) for nine SNP alleles at three independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; Poverall: 2.47 × 10(-06)/Pfemales: 3.45 × 10(-07)/Pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet-induced obese (DIO) mice as compared with age-matched lean controls. We observed no evidence for associations for the look-up of BMI-related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation.Molecular Psychiatry advance online publication, 17 May 2016; doi:10.1038/mp.2016.71.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/27184124?dopt=Abstract ER - TY - JOUR T1 - Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function. JF - Nat Commun Y1 - 2016 A1 - Pattaro, Cristian A1 - Teumer, Alexander A1 - Gorski, Mathias A1 - Chu, Audrey Y A1 - Li, Man A1 - Mijatovic, Vladan A1 - Garnaas, Maija A1 - Tin, Adrienne A1 - Sorice, Rossella A1 - Li, Yong A1 - Taliun, Daniel A1 - Olden, Matthias A1 - Foster, Meredith A1 - Yang, Qiong A1 - Chen, Ming-Huei A1 - Pers, Tune H A1 - Johnson, Andrew D A1 - Ko, Yi-An A1 - Fuchsberger, Christian A1 - Tayo, Bamidele A1 - Nalls, Michael A1 - Feitosa, Mary F A1 - Isaacs, Aaron A1 - Dehghan, Abbas A1 - d'Adamo, Pio A1 - Adeyemo, Adebowale A1 - Dieffenbach, Aida Karina A1 - Zonderman, Alan B A1 - Nolte, Ilja M A1 - van der Most, Peter J A1 - Wright, Alan F A1 - Shuldiner, Alan R A1 - Morrison, Alanna C A1 - Hofman, Albert A1 - Smith, Albert V A1 - Dreisbach, Albert W A1 - Franke, Andre A1 - Uitterlinden, André G A1 - Metspalu, Andres A1 - Tönjes, Anke A1 - Lupo, Antonio A1 - Robino, Antonietta A1 - Johansson, Åsa A1 - Demirkan, Ayse A1 - Kollerits, Barbara A1 - Freedman, Barry I A1 - Ponte, Belen A1 - Oostra, Ben A A1 - Paulweber, Bernhard A1 - Krämer, Bernhard K A1 - Mitchell, Braxton D A1 - Buckley, Brendan M A1 - Peralta, Carmen A A1 - Hayward, Caroline A1 - Helmer, Catherine A1 - Rotimi, Charles N A1 - Shaffer, Christian M A1 - Müller, Christian A1 - Sala, Cinzia A1 - van Duijn, Cornelia M A1 - Saint-Pierre, Aude A1 - Ackermann, Daniel A1 - Shriner, Daniel A1 - Ruggiero, Daniela A1 - Toniolo, Daniela A1 - Lu, Yingchang A1 - Cusi, Daniele A1 - Czamara, Darina A1 - Ellinghaus, David A1 - Siscovick, David S A1 - Ruderfer, Douglas A1 - Gieger, Christian A1 - Grallert, Harald A1 - Rochtchina, Elena A1 - Atkinson, Elizabeth J A1 - Holliday, Elizabeth G A1 - Boerwinkle, Eric A1 - Salvi, Erika A1 - Bottinger, Erwin P A1 - Murgia, Federico A1 - Rivadeneira, Fernando A1 - Ernst, Florian A1 - Kronenberg, Florian A1 - Hu, Frank B A1 - Navis, Gerjan J A1 - Curhan, Gary C A1 - Ehret, George B A1 - Homuth, Georg A1 - Coassin, Stefan A1 - Thun, Gian-Andri A1 - Pistis, Giorgio A1 - Gambaro, Giovanni A1 - Malerba, Giovanni A1 - Montgomery, Grant W A1 - Eiriksdottir, Gudny A1 - Jacobs, Gunnar A1 - Li, Guo A1 - Wichmann, H-Erich A1 - Campbell, Harry A1 - Schmidt, Helena A1 - Wallaschofski, Henri A1 - Völzke, Henry A1 - Brenner, Hermann A1 - Kroemer, Heyo K A1 - Kramer, Holly A1 - Lin, Honghuang A1 - Leach, I Mateo A1 - Ford, Ian A1 - Guessous, Idris A1 - Rudan, Igor A1 - Prokopenko, Inga A1 - Borecki, Ingrid A1 - Heid, Iris M A1 - Kolcic, Ivana A1 - Persico, Ivana A1 - Jukema, J Wouter A1 - Wilson, James F A1 - Felix, Janine F A1 - Divers, Jasmin A1 - Lambert, Jean-Charles A1 - Stafford, Jeanette M A1 - Gaspoz, Jean-Michel A1 - Smith, Jennifer A A1 - Faul, Jessica D A1 - Wang, Jie Jin A1 - Ding, Jingzhong A1 - Hirschhorn, Joel N A1 - Attia, John A1 - Whitfield, John B A1 - Chalmers, John A1 - Viikari, Jorma A1 - Coresh, Josef A1 - Denny, Joshua C A1 - Karjalainen, Juha A1 - Fernandes, Jyotika K A1 - Endlich, Karlhans A1 - Butterbach, Katja A1 - Keene, Keith L A1 - Lohman, Kurt A1 - Portas, Laura A1 - Launer, Lenore J A1 - Lyytikäinen, Leo-Pekka A1 - Yengo, Loic A1 - Franke, Lude A1 - Ferrucci, Luigi A1 - Rose, Lynda M A1 - Kedenko, Lyudmyla A1 - Rao, Madhumathi A1 - Struchalin, Maksim A1 - Kleber, Marcus E A1 - Cavalieri, Margherita A1 - Haun, Margot A1 - Cornelis, Marilyn C A1 - Ciullo, Marina A1 - Pirastu, Mario A1 - de Andrade, Mariza A1 - McEvoy, Mark A A1 - Woodward, Mark A1 - Adam, Martin A1 - Cocca, Massimiliano A1 - Nauck, Matthias A1 - Imboden, Medea A1 - Waldenberger, Melanie A1 - Pruijm, Menno A1 - Metzger, Marie A1 - Stumvoll, Michael A1 - Evans, Michele K A1 - Sale, Michele M A1 - Kähönen, Mika A1 - Boban, Mladen A1 - Bochud, Murielle A1 - Rheinberger, Myriam A1 - Verweij, Niek A1 - Bouatia-Naji, Nabila A1 - Martin, Nicholas G A1 - Hastie, Nick A1 - Probst-Hensch, Nicole A1 - Soranzo, Nicole A1 - Devuyst, Olivier A1 - Raitakari, Olli A1 - Gottesman, Omri A1 - Franco, Oscar H A1 - Polasek, Ozren A1 - Gasparini, Paolo A1 - Munroe, Patricia B A1 - Ridker, Paul M A1 - Mitchell, Paul A1 - Muntner, Paul A1 - Meisinger, Christa A1 - Smit, Johannes H A1 - Kovacs, Peter A1 - Wild, Philipp S A1 - Froguel, Philippe A1 - Rettig, Rainer A1 - Mägi, Reedik A1 - Biffar, Reiner A1 - Schmidt, Reinhold A1 - Middelberg, Rita P S A1 - Carroll, Robert J A1 - Penninx, Brenda W A1 - Scott, Rodney J A1 - Katz, Ronit A1 - Sedaghat, Sanaz A1 - Wild, Sarah H A1 - Kardia, Sharon L R A1 - Ulivi, Sheila A1 - Hwang, Shih-Jen A1 - Enroth, Stefan A1 - Kloiber, Stefan A1 - Trompet, Stella A1 - Stengel, Bénédicte A1 - Hancock, Stephen J A1 - Turner, Stephen T A1 - Rosas, Sylvia E A1 - Stracke, Sylvia A1 - Harris, Tamara B A1 - Zeller, Tanja A1 - Zemunik, Tatijana A1 - Lehtimäki, Terho A1 - Illig, Thomas A1 - Aspelund, Thor A1 - Nikopensius, Tiit A1 - Esko, Tõnu A1 - Tanaka, Toshiko A1 - Gyllensten, Ulf A1 - Völker, Uwe A1 - Emilsson, Valur A1 - Vitart, Veronique A1 - Aalto, Ville A1 - Gudnason, Vilmundur A1 - Chouraki, Vincent A1 - Chen, Wei-Min A1 - Igl, Wilmar A1 - März, Winfried A1 - Koenig, Wolfgang A1 - Lieb, Wolfgang A1 - Loos, Ruth J F A1 - Liu, Yongmei A1 - Snieder, Harold A1 - Pramstaller, Peter P A1 - Parsa, Afshin A1 - O'Connell, Jeffrey R A1 - Susztak, Katalin A1 - Hamet, Pavel A1 - Tremblay, Johanne A1 - de Boer, Ian H A1 - Böger, Carsten A A1 - Goessling, Wolfram A1 - Chasman, Daniel I A1 - Köttgen, Anna A1 - Kao, W H Linda A1 - Fox, Caroline S KW - Gene Expression Regulation KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Renal Insufficiency, Chronic AB -

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.

VL - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26831199?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study identifies 74 loci associated with educational attainment. JF - Nature Y1 - 2016 A1 - Okbay, Aysu A1 - Beauchamp, Jonathan P A1 - Fontana, Mark Alan A1 - Lee, James J A1 - Pers, Tune H A1 - Rietveld, Cornelius A A1 - Turley, Patrick A1 - Chen, Guo-Bo A1 - Emilsson, Valur A1 - Meddens, S Fleur W A1 - Oskarsson, Sven A1 - Pickrell, Joseph K A1 - Thom, Kevin A1 - Timshel, Pascal A1 - de Vlaming, Ronald A1 - Abdellaoui, Abdel A1 - Ahluwalia, Tarunveer S A1 - Bacelis, Jonas A1 - Baumbach, Clemens A1 - Bjornsdottir, Gyda A1 - Brandsma, Johannes H A1 - Pina Concas, Maria A1 - Derringer, Jaime A1 - Furlotte, Nicholas A A1 - Galesloot, Tessel E A1 - Girotto, Giorgia A1 - Gupta, Richa A1 - Hall, Leanne M A1 - Harris, Sarah E A1 - Hofer, Edith A1 - Horikoshi, Momoko A1 - Huffman, Jennifer E A1 - Kaasik, Kadri A1 - Kalafati, Ioanna P A1 - Karlsson, Robert A1 - Kong, Augustine A1 - Lahti, Jari A1 - van der Lee, Sven J A1 - deLeeuw, Christiaan A1 - Lind, Penelope A A1 - Lindgren, Karl-Oskar A1 - Liu, Tian A1 - Mangino, Massimo A1 - Marten, Jonathan A1 - Mihailov, Evelin A1 - Miller, Michael B A1 - van der Most, Peter J A1 - Oldmeadow, Christopher A1 - Payton, Antony A1 - Pervjakova, Natalia A1 - Peyrot, Wouter J A1 - Qian, Yong A1 - Raitakari, Olli A1 - Rueedi, Rico A1 - Salvi, Erika A1 - Schmidt, Börge A1 - Schraut, Katharina E A1 - Shi, Jianxin A1 - Smith, Albert V A1 - Poot, Raymond A A1 - St Pourcain, Beate A1 - Teumer, Alexander A1 - Thorleifsson, Gudmar A1 - Verweij, Niek A1 - Vuckovic, Dragana A1 - Wellmann, Juergen A1 - Westra, Harm-Jan A1 - Yang, Jingyun A1 - Zhao, Wei A1 - Zhu, Zhihong A1 - Alizadeh, Behrooz Z A1 - Amin, Najaf A1 - Bakshi, Andrew A1 - Baumeister, Sebastian E A1 - Biino, Ginevra A1 - Bønnelykke, Klaus A1 - Boyle, Patricia A A1 - Campbell, Harry A1 - Cappuccio, Francesco P A1 - Davies, Gail A1 - De Neve, Jan-Emmanuel A1 - Deloukas, Panos A1 - Demuth, Ilja A1 - Ding, Jun A1 - Eibich, Peter A1 - Eisele, Lewin A1 - Eklund, Niina A1 - Evans, David M A1 - Faul, Jessica D A1 - Feitosa, Mary F A1 - Forstner, Andreas J A1 - Gandin, Ilaria A1 - Gunnarsson, Bjarni A1 - Halldórsson, Bjarni V A1 - Harris, Tamara B A1 - Heath, Andrew C A1 - Hocking, Lynne J A1 - Holliday, Elizabeth G A1 - Homuth, Georg A1 - Horan, Michael A A1 - Hottenga, Jouke-Jan A1 - de Jager, Philip L A1 - Joshi, Peter K A1 - Jugessur, Astanand A1 - Kaakinen, Marika A A1 - Kähönen, Mika A1 - Kanoni, Stavroula A1 - Keltigangas-Järvinen, Liisa A1 - Kiemeney, Lambertus A L M A1 - Kolcic, Ivana A1 - Koskinen, Seppo A1 - Kraja, Aldi T A1 - Kroh, Martin A1 - Kutalik, Zoltán A1 - Latvala, Antti A1 - Launer, Lenore J A1 - Lebreton, Maël P A1 - Levinson, Douglas F A1 - Lichtenstein, Paul A1 - Lichtner, Peter A1 - Liewald, David C M A1 - Loukola, Anu A1 - Madden, Pamela A A1 - Mägi, Reedik A1 - Mäki-Opas, Tomi A1 - Marioni, Riccardo E A1 - Marques-Vidal, Pedro A1 - Meddens, Gerardus A A1 - McMahon, George A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Milaneschi, Yusplitri A1 - Milani, Lili A1 - Montgomery, Grant W A1 - Myhre, Ronny A1 - Nelson, Christopher P A1 - Nyholt, Dale R A1 - Ollier, William E R A1 - Palotie, Aarno A1 - Paternoster, Lavinia A1 - Pedersen, Nancy L A1 - Petrovic, Katja E A1 - Porteous, David J A1 - Räikkönen, Katri A1 - Ring, Susan M A1 - Robino, Antonietta A1 - Rostapshova, Olga A1 - Rudan, Igor A1 - Rustichini, Aldo A1 - Salomaa, Veikko A1 - Sanders, Alan R A1 - Sarin, Antti-Pekka A1 - Schmidt, Helena A1 - Scott, Rodney J A1 - Smith, Blair H A1 - Smith, Jennifer A A1 - Staessen, Jan A A1 - Steinhagen-Thiessen, Elisabeth A1 - Strauch, Konstantin A1 - Terracciano, Antonio A1 - Tobin, Martin D A1 - Ulivi, Sheila A1 - Vaccargiu, Simona A1 - Quaye, Lydia A1 - van Rooij, Frank J A A1 - Venturini, Cristina A1 - Vinkhuyzen, Anna A E A1 - Völker, Uwe A1 - Völzke, Henry A1 - Vonk, Judith M A1 - Vozzi, Diego A1 - Waage, Johannes A1 - Ware, Erin B A1 - Willemsen, Gonneke A1 - Attia, John R A1 - Bennett, David A A1 - Berger, Klaus A1 - Bertram, Lars A1 - Bisgaard, Hans A1 - Boomsma, Dorret I A1 - Borecki, Ingrid B A1 - Bültmann, Ute A1 - Chabris, Christopher F A1 - Cucca, Francesco A1 - Cusi, Daniele A1 - Deary, Ian J A1 - Dedoussis, George V A1 - van Duijn, Cornelia M A1 - Eriksson, Johan G A1 - Franke, Barbara A1 - Franke, Lude A1 - Gasparini, Paolo A1 - Gejman, Pablo V A1 - Gieger, Christian A1 - Grabe, Hans-Jörgen A1 - Gratten, Jacob A1 - Groenen, Patrick J F A1 - Gudnason, Vilmundur A1 - van der Harst, Pim A1 - Hayward, Caroline A1 - Hinds, David A A1 - Hoffmann, Wolfgang A1 - Hyppönen, Elina A1 - Iacono, William G A1 - Jacobsson, Bo A1 - Järvelin, Marjo-Riitta A1 - Jöckel, Karl-Heinz A1 - Kaprio, Jaakko A1 - Kardia, Sharon L R A1 - Lehtimäki, Terho A1 - Lehrer, Steven F A1 - Magnusson, Patrik K E A1 - Martin, Nicholas G A1 - McGue, Matt A1 - Metspalu, Andres A1 - Pendleton, Neil A1 - Penninx, Brenda W J H A1 - Perola, Markus A1 - Pirastu, Nicola A1 - Pirastu, Mario A1 - Polasek, Ozren A1 - Posthuma, Danielle A1 - Power, Christine A1 - Province, Michael A A1 - Samani, Nilesh J A1 - Schlessinger, David A1 - Schmidt, Reinhold A1 - Sørensen, Thorkild I A A1 - Spector, Tim D A1 - Stefansson, Kari A1 - Thorsteinsdottir, Unnur A1 - Thurik, A Roy A1 - Timpson, Nicholas J A1 - Tiemeier, Henning A1 - Tung, Joyce Y A1 - Uitterlinden, André G A1 - Vitart, Veronique A1 - Vollenweider, Peter A1 - Weir, David R A1 - Wilson, James F A1 - Wright, Alan F A1 - Conley, Dalton C A1 - Krueger, Robert F A1 - Davey Smith, George A1 - Hofman, Albert A1 - Laibson, David I A1 - Medland, Sarah E A1 - Meyer, Michelle N A1 - Yang, Jian A1 - Johannesson, Magnus A1 - Visscher, Peter M A1 - Esko, Tõnu A1 - Koellinger, Philipp D A1 - Cesarini, David A1 - Benjamin, Daniel J KW - Alzheimer Disease KW - Bipolar Disorder KW - Brain KW - Cognition KW - Computational Biology KW - Educational Status KW - Fetus KW - Gene Expression Regulation KW - Gene-Environment Interaction KW - Genome-Wide Association Study KW - Great Britain KW - Humans KW - Molecular Sequence Annotation KW - Polymorphism, Single Nucleotide KW - Schizophrenia AB -

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

VL - 533 IS - 7604 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27225129?dopt=Abstract ER - TY - JOUR T1 - A Genome-Wide Association Study in isolated populations reveals new genes associated to common food likings. JF - Rev Endocr Metab Disord Y1 - 2016 A1 - Pirastu, Nicola A1 - Kooyman, Maarten A1 - Traglia, Michela A1 - Robino, Antonietta A1 - Willems, Sara M A1 - Pistis, Giorgio A1 - Amin, Najaf A1 - Sala, Cinzia A1 - Karssen, Lennart C A1 - van Duijn, Cornelia A1 - Toniolo, Daniela A1 - Gasparini, Paolo AB -

Food preferences are the first factor driving food choice and thus nutrition. They involve numerous different senses such as taste and olfaction as well as various other factors such as personal experiences and hedonistic aspects. Although it is clear that several of these have a genetic basis, up to now studies have focused mostly on the effects of polymorphisms of taste receptor genes. Therefore, we have carried out one of the first large scale (4611 individuals) GWAS on food likings assessed for 20 specific food likings belonging to 4 different categories (vegetables, fatty, dairy and bitter). A two-step meta-analysis using three different isolated populations from Italy for the discovery step and two populations from The Netherlands and Central Asia for replication, revealed 15 independent genome-wide significant loci (p < 5 × 10(-8)) for 12 different foods. None of the identified genes coded for either taste or olfactory receptors suggesting that genetics impacts in determining food likings in a much broader way than simple differences in taste perception. These results represent a further step in uncovering the genes that underlie liking of common foods that in the end will greatly help understanding the genetics of human nutrition in general.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/27129595?dopt=Abstract ER - TY - JOUR T1 - Letter to the editor: Outbreak of a new measles B3 variant in the Roma/Sinti population with transmission in the nosocomial setting, Italy, November 2015 to April 2016. JF - Euro Surveill Y1 - 2016 A1 - Monasta, Lorenzo A1 - Knowles, Alessandra VL - 21 IS - 27 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27418558?dopt=Abstract ER - TY - JOUR T1 - MBL2 genetic polymorphisms and HIV-1 mother-to-child transmission in Zambia. JF - Immunol Res Y1 - 2016 A1 - Zupin, Luisa A1 - Polesello, Vania A1 - Segat, Ludovica A1 - Kuhn, Louise A1 - Crovella, Sergio AB -

Since antiretroviral drugs have been introduced to prevent mother-to-child transmission, the risk of HIV-1 infection in infants has decreased considerably worldwide. Nevertheless, many factors are involved in viral transmission and host susceptibility to infection. The immune system and its components, including mannose binding protein C (encoding by MBL2 gene), are already known to play an important role in this scenario. In the present study, 313 children and 98 of their mothers from Zambia were genotyped for the MBL2 promoter HL (rs11003125) and XY (rs7096206) polymorphisms and exon 1 D (rs5030737, at codon 52) B (rs1800450, at codon 54) and C (rs1800451, at codon 57) polymorphisms in order to investigate the potential role of these genetic variants in HIV-1 mother-to-child transmission. No statistical significant association was observed comparing transmitter and non-transmitter mothers and also confronting HIV-positive and HIV-negative children. The findings of the current study obtained on mother and children from Zambia evidence lack of association between MBL2 functional polymorphisms and HIV-1 mother-to-child transmission.

VL - 64 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26740328?dopt=Abstract ER - TY - JOUR T1 - Non-additive genome-wide association scan reveals a new gene associated with habitual coffee consumption. JF - Sci Rep Y1 - 2016 A1 - Pirastu, Nicola A1 - Kooyman, Maarten A1 - Robino, Antonietta A1 - van der Spek, Ashley A1 - Navarini, Luciano A1 - Amin, Najaf A1 - Karssen, Lennart C A1 - van Duijn, Cornelia M A1 - Gasparini, Paolo AB -

Coffee is one of the most consumed beverages world-wide and one of the primary sources of caffeine intake. Given its important health and economic impact, the underlying genetics of its consumption has been widely studied. Despite these efforts, much has still to be uncovered. In particular, the use of non-additive genetic models may uncover new information about the genetic variants driving coffee consumption. We have conducted a genome-wide association study in two Italian populations using additive, recessive and dominant models for analysis. This has uncovered a significant association in the PDSS2 gene under the recessive model that has been replicated in an independent cohort from the Netherlands (ERF). The identified gene has been shown to negatively regulate the expression of the caffeine metabolism genes and can thus be linked to coffee consumption. Further bioinformatics analysis of eQTL and histone marks from Roadmap data has evidenced a possible role of the identified SNPs in regulating PDSS2 gene expression through enhancers present in its intron. Our results highlight a novel gene which regulates coffee consumption by regulating the expression of the genes linked to caffeine metabolism. Further studies will be needed to clarify the biological mechanism which links PDSS2 and coffee consumption.

VL - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27561104?dopt=Abstract ER - TY - JOUR T1 - Nonmuscle Myosin Heavy Chain IIA Mutation Predicts Severity and Progression of Sensorineural Hearing Loss in Patients With MYH9-Related Disease. JF - Ear Hear Y1 - 2016 A1 - Verver, Eva J J A1 - Topsakal, Vedat A1 - Kunst, Henricus P M A1 - Huygen, Patrick L M A1 - Heller, Paula G A1 - Pujol-Moix, Núria A1 - Savoia, Anna A1 - Benazzo, Marco A1 - Fierro, Tiziana A1 - Grolman, Wilko A1 - Gresele, Paolo A1 - Pecci, Alessandro AB -

OBJECTIVES: MYH9-related disease (MYH9-RD) is an autosomal- dominant disorder deriving from mutations in MYH9, the gene for the nonmuscle myosin heavy chain (NMMHC)-IIA. MYH9-RD has a complex phenotype including congenital features, such as thrombocytopenia, and noncongenital manifestations, namely sensorineural hearing loss (SNHL), nephropathy, cataract, and liver abnormalities. The disease is caused by a limited number of mutations affecting different regions of the NMMHC-IIA protein. SNHL is the most frequent noncongenital manifestation of MYH9-RD. However, only scarce and anecdotal information is currently available about the clinical and audiometric features of SNHL of MYH9-RD subjects. The objective of this study was to investigate the severity and propensity for progression of SNHL in a large series of MYH9-RD patients in relation to the causative NMMHC-IIA mutations.

DESIGN: This study included the consecutive patients diagnosed with MYH9-RD between July 2007 and March 2012 at four participating institutions. A total of 115 audiograms were analyzed from 63 patients belonging to 45 unrelated families with different NMMHC-IIA mutations. Cross-sectional analyses of audiograms were performed. Regression analysis was performed, and age-related typical audiograms (ARTAs) were derived to characterize the type of SNHL associated with different mutations.

RESULTS: Severity of SNHL appeared to depend on the specific NMMHC-IIA mutation. Patients carrying substitutions at the residue R702 located in the short functional SH1 helix had the most severe degree of SNHL, whereas patients with the p.E1841K substitution in the coiled-coil region or mutations at the nonhelical tailpiece presented a mild degree of SNHL even at advanced age. The authors also disclosed the effects of different amino acid changes at the same residue: for instance, individuals with the p.R702C mutation had more severe SNHL than those with the p.R702H mutation, and the p.R1165L substitution was associated with a higher degree of hearing loss than the p.R1165C. In general, mild SNHL was associated with a fairly flat audiogram configuration, whereas severe SNHL correlated with downsloping configurations. ARTA plots showed that the most progressive type of SNHL was associated with the p.R702C, the p.R702H, and the p.R1165L substitutions, whereas the p.R1165C mutation correlated with a milder, nonprogressive type of SNHL than the p.R1165L. ARTA for the p.E1841K mutation demonstrated a mild degree of SNHL with only mild progression, whereas the ARTA for the mutations at the nonhelical tailpiece did not show any substantial progression.

CONCLUSIONS: These data provide useful tools to predict the progression and the expected degree of severity of SNHL in individual MYH9-RD patients, which is especially relevant in young patients. Consequences in clinical practice are important not only for appropriate patient counseling but also for development of customized, genotype-driven clinical management. The authors recently reported that cochlear implantation has a good outcome in MYH9-RD patients; thus, stricter follow-up and earlier intervention are recommended for patients with unfavorable genotypes.

VL - 37 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26226608?dopt=Abstract ER - TY - JOUR T1 - The one-step synthesis and surface functionalization of dumbbell-like gold-iron oxide nanoparticles: a chitosan-based nanotheranostic system. JF - Chem Commun (Camb) Y1 - 2016 A1 - Kostevsek, Nina A1 - Locatelli, Erica A1 - Garrovo, Chiara A1 - Arena, Francesca A1 - Monaco, Ilaria A1 - Nikolov, Ivaylo Petrov A1 - Sturm, Saso A1 - Zuzek Rozman, Kristina A1 - Lorusso, Vito A1 - Giustetto, Pierangela A1 - Bardini, Paola A1 - Biffi, Stefania A1 - Comes Franchini, Mauro AB -

The first one-step synthesis of dumbbell-like gold-iron oxide nanoparticles has been reported here. Surface functionalization with a biocompatible chitosan matrix allowed us to obtain a novel targetable diagnostic and therapeutic tool.

VL - 52 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26524586?dopt=Abstract ER - TY - JOUR T1 - Plant Elite Squad: First Defense Line and Resistance Genes - Identification, Diversity and Functional Roles. JF - Curr Protein Pept Sci Y1 - 2016 A1 - Wanderley-Nogueira, Ana Carolina A1 - Bezerra-Neto, João Pacífico A1 - Kido, Éderson Akio A1 - de Araújo, Flávia Tadeu A1 - Amorim, Lidiane Lindinalva Barbosa A1 - Crovella, Sergio A1 - Benko-Iseppon, Ana Maria AB -

Plants exhibit sensitive mechanisms to respond to environmental stresses, presenting some specific and non-specific reactions when attacked by pathogens, including organisms from different classes and complexity, as viroids, viruses, bacteria, fungi and nematodes. A crucial step to define the fate of the plant facing an invading pathogen is the activation of a compatible Resistance (R) gene, the focus of the present review. Different aspects regarding R-genes and their products are discussed, including pathogen recognition mechanisms, signaling and effects on induced and constitutive defense processes, splicing and post transcriptional mechanisms involved. There are still countless challenges to the complete understanding of the mechanisms involving R-genes in plants, in particular those related to the interactions with other genes of the pathogen and of the host itself, their regulation, acting mechanisms at transcriptional and post-transcriptional levels, as well as the influence of other types of stress over their regulation. A magnification of knowledge is expected when considering the novel information from the omics and systems biology.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/27455974?dopt=Abstract ER - TY - JOUR T1 - Plants Defense-related Cyclic Peptides: Diversity, Structure and Applications. JF - Curr Protein Pept Sci Y1 - 2016 A1 - Maria, Ana Carolina Wanderley-Nogueira A1 - Bezerra-Neto, João Pacífico A1 - Kido, Éderson Akio A1 - de Araújo, Flávia Tadeu A1 - Amorim, Lidiane Lindinalva Barbosa A1 - Crovella, Sergio A1 - Benko-Iseppon, Ana Maria AB -

Plant growth is prone to several unfavorable factors that may compromise or impair development and survival, including abiotic or biotic stressors. Aiming at defending themselves, plants have developed several strategies to survive and adapt to such adversities. Cyclotides are a family of plant-derived proteins that exhibit a diverse range of biological activities including antimicrobial and insecticidal activities that actively participate in plant defense processes. Three main categories of peptides have been described: (i) Cyclotides (ii) Sunflower Trypsin Inhibitor (SFTI) and (iii) peptides MCoTI-I and II, from Momordica cochinchinensis. They comprise proteins of approximately 30 amino acids, containing a head-to-tail cyclized backbone, with three disulfide bonds configured in a cystine knot topology, therefore bearing greater peptide stability. Given their features and multifunctionality, cyclotides stand out as promising sources for the discovery of new antimicrobial agents. The present review describes cyclotide occurrence, abundance and action in plants, also their diversity and evolution. Considerations regarding their use in the context of biomedical and agronomical sciences uses are also presented.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/27455973?dopt=Abstract ER - TY - JOUR T1 - Protective Role of BST2 Polymorphisms in Mother-to-Child Transmission of HIV-1 and Adult AIDS Progression. JF - J Acquir Immune Defic Syndr Y1 - 2016 A1 - Kamada, Anselmo J A1 - Bianco, Anna M A1 - Zupin, Luisa A1 - Girardelli, Martina A1 - Matte, Maria C C A1 - Medeiros, Rúbia Marília de A1 - Almeida, Sabrina Esteves de Matos A1 - Rocha, Marineide M A1 - Segat, Ludovica A1 - Chies, José A B A1 - Kuhn, Louise A1 - Crovella, Sergio AB -

Bone marrow stromal cell antigen-2 (BST-2)/Tetherin is a restriction factor that prevents Human immunodeficiency virus type 1 (HIV-1) release from infected cells and mediates pro-inflammatory cytokine production. This study investigated the risk conferred by single nucleotide polymorphisms (rs919266, rs9192677, and rs9576) at BST-2 coding gene (BST2) in HIV-1 mother-to-child transmission and in disease progression. Initially, 101 HIV-1+ pregnant women and 331 neonates exposed to HIV-1 from Zambia were enrolled. Additional BST2 single nucleotide polymorphism analyses were performed in 2 cohorts with acquired immunodeficiency syndrome (AIDS) progression: an adult Brazilian cohort (37 rapid, 30 chronic and 21 long-term non-progressors) and an Italian pediatric cohort (21 rapid and 67 slow progressors). The rs9576A allele was nominally associated with protection during breastfeeding (P = 0.019) and individuals carrying rs919266 GA showed slower progression to AIDS (P = 0.033). Despite the influence of rs919266 and rs9576 on BST2 expression being still undetermined, a preventive role by BST2 polymorphisms was found during HIV-1 infection.

VL - 72 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26885809?dopt=Abstract ER - TY - JOUR T1 - Putative modifier genes in mevalonate kinase deficiency. JF - Mol Med Rep Y1 - 2016 A1 - Marcuzzi, Annalisa A1 - Vozzi, Diego A1 - Girardelli, Martina A1 - Tricarico, Paola Maura A1 - Knowles, Alessandra A1 - Crovella, Sergio A1 - Vuch, Josef A1 - Tommasini, Alberto A1 - Piscianz, Elisa A1 - Bianco, Anna Monica AB -

Mevalonate kinase deficiency (MKD) is an autosomal recessive auto‑inflammatory disease, caused by impairment of the mevalonate pathway. Although the molecular mechanism remains to be elucidated, there is clinical evidence suggesting that other regulatory genes may be involved in determining the phenotype. The identification of novel target genes may explain non‑homogeneous genotype‑phenotype correlations, and provide evidence in support of the hypothesis that novel regulatory genes predispose or amplify deregulation of the mevalonate pathway in this orphan disease. In the present study, DNA samples were obtained from five patients with MKD, which were then analyzed using whole exome sequencing. A missense variation in the PEX11γ gene was observed in homozygosis in P2, possibly correlating with visual blurring. The UNG rare gene variant was detected in homozygosis in P5, without correlating with a specific clinical phenotype. A number of other variants were found in the five analyzed DNA samples from the MKD patients, however no correlation with the phenotype was established. The results of the presents study suggested that further analysis, using next generation sequencing approaches, is required on a larger sample size of patients with MKD, who share the same MVK mutations and exhibit 'extreme' clinical phenotypes. As MVK mutations may be associated with MKD, the identification of specific modifier genes may assist in providing an earlier diagnosis.

VL - 13 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26935981?dopt=Abstract ER - TY - JOUR T1 - A reference panel of 64,976 haplotypes for genotype imputation. JF - Nat Genet Y1 - 2016 A1 - McCarthy, Shane A1 - Das, Sayantan A1 - Kretzschmar, Warren A1 - Delaneau, Olivier A1 - Wood, Andrew R A1 - Teumer, Alexander A1 - Kang, Hyun Min A1 - Fuchsberger, Christian A1 - Danecek, Petr A1 - Sharp, Kevin A1 - Luo, Yang A1 - Sidore, Carlo A1 - Kwong, Alan A1 - Timpson, Nicholas A1 - Koskinen, Seppo A1 - Vrieze, Scott A1 - Scott, Laura J A1 - Zhang, He A1 - Mahajan, Anubha A1 - Veldink, Jan A1 - Peters, Ulrike A1 - Pato, Carlos A1 - van Duijn, Cornelia M A1 - Gillies, Christopher E A1 - Gandin, Ilaria A1 - Mezzavilla, Massimo A1 - Gilly, Arthur A1 - Cocca, Massimiliano A1 - Traglia, Michela A1 - Angius, Andrea A1 - Barrett, Jeffrey C A1 - Boomsma, Dorrett A1 - Branham, Kari A1 - Breen, Gerome A1 - Brummett, Chad M A1 - Busonero, Fabio A1 - Campbell, Harry A1 - Chan, Andrew A1 - Chen, Sai A1 - Chew, Emily A1 - Collins, Francis S A1 - Corbin, Laura J A1 - Smith, George Davey A1 - Dedoussis, George A1 - Dörr, Marcus A1 - Farmaki, Aliki-Eleni A1 - Ferrucci, Luigi A1 - Forer, Lukas A1 - Fraser, Ross M A1 - Gabriel, Stacey A1 - Levy, Shawn A1 - Groop, Leif A1 - Harrison, Tabitha A1 - Hattersley, Andrew A1 - Holmen, Oddgeir L A1 - Hveem, Kristian A1 - Kretzler, Matthias A1 - Lee, James C A1 - McGue, Matt A1 - Meitinger, Thomas A1 - Melzer, David A1 - Min, Josine L A1 - Mohlke, Karen L A1 - Vincent, John B A1 - Nauck, Matthias A1 - Nickerson, Deborah A1 - Palotie, Aarno A1 - Pato, Michele A1 - Pirastu, Nicola A1 - McInnis, Melvin A1 - Richards, J Brent A1 - Sala, Cinzia A1 - Salomaa, Veikko A1 - Schlessinger, David A1 - Schoenherr, Sebastian A1 - Slagboom, P Eline A1 - Small, Kerrin A1 - Spector, Timothy A1 - Stambolian, Dwight A1 - Tuke, Marcus A1 - Tuomilehto, Jaakko A1 - Van den Berg, Leonard H A1 - van Rheenen, Wouter A1 - Völker, Uwe A1 - Wijmenga, Cisca A1 - Toniolo, Daniela A1 - Zeggini, Eleftheria A1 - Gasparini, Paolo A1 - Sampson, Matthew G A1 - Wilson, James F A1 - Frayling, Timothy A1 - de Bakker, Paul I W A1 - Swertz, Morris A A1 - McCarroll, Steven A1 - Kooperberg, Charles A1 - Dekker, Annelot A1 - Altshuler, David A1 - Willer, Cristen A1 - Iacono, William A1 - Ripatti, Samuli A1 - Soranzo, Nicole A1 - Walter, Klaudia A1 - Swaroop, Anand A1 - Cucca, Francesco A1 - Anderson, Carl A A1 - Myers, Richard M A1 - Boehnke, Michael A1 - McCarthy, Mark I A1 - Durbin, Richard AB -

We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/27548312?dopt=Abstract ER - TY - JOUR T1 - Resistance (R) Genes: Applications and Prospects for Plant Biotechnology and Breeding. JF - Curr Protein Pept Sci Y1 - 2016 A1 - Pandolfi, Valesca A1 - Neto, José Ribamar Costa Ferreira A1 - Silva, Manassés Daniel A1 - Amorim, Lidiane Lindinalva Barbosa A1 - Wanderley-Nogueira, Ana Carolina A1 - de Oliveira Silva, Roberta Lane A1 - Kido, Éderson Akio A1 - Crovella, Sergio A1 - Iseppon, Ana Maria Benko AB -

The discovery of novel plant resistance (R) genes (including their homologs and analogs) opened interesting possibilities for controlling plant diseases caused by several pathogens. However, due to environmental pressure and high selection operated by pathogens, several crop plants have lost specificity, broad-spectrum or durability of resistance. On the other hand, the advances in plant genome sequencing and biotechnological approaches, combined with the increasing knowledge on R-genes have provided new insights on their applications for plant genetic breeding, allowing the identification and implementation of novel and efficient strategies that enhance or optimize their use for efficiently controlling plant diseases. The present review focuses on main perspectives of application of R-genes and its co-players for the acquisition of resistance to pathogens in cultivated plants, with emphasis on biotechnological inferences, including transgenesis, cisgenesis, directed mutagenesis and gene editing, with examples of success and challenges to be faced.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/27455971?dopt=Abstract ER - TY - JOUR T1 - Snakin: Structure, Roles and Applications of a Plant Antimicrobial Peptide. JF - Curr Protein Pept Sci Y1 - 2016 A1 - Oliveira-Lima, Marx A1 - Benko-Iseppon, Ana Maria A1 - Neto, José Ribamar Costa Ferreira A1 - Rodríguez-Decuadro, Susana A1 - Kido, Éderson Akio A1 - Crovella, Sergio A1 - Pandolfi, Valesca AB -

Snakins are plant antimicrobial peptides (AMPs) of the Snakin/GASA family, formed by three distinct regions: an N-terminal signal peptide; a variable site; and the GASA domain in the C-terminal region composed by twelve conserved cysteine residues that contribute to the biochemical stability of the molecule. These peptides are known to play different roles in response to a variety of biotic (i.e. induced by bacteria, fungi and nematode pathogens) and abiotic (salinity, drought and ROS) stressors, as well as in crosstalk promoted by plant hormones, with emphasis on abscisic and salicylic acid (ABA and SA, respectively). Such properties make snakin/GASA members promising biotechnological sources for potential therapeutic and agricultural applications. However, information regarding their tertiary structure, mode of action and function are not yet completely elucidated. The present review presents aspects of snakin structure, expression, functional studies and perspectives about the potential applications for agricultural and medical purposes.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/27323806?dopt=Abstract ER - TY - JOUR T1 - Synchrotron X-ray microscopy reveals early calcium and iron interaction with crocidolite fibers in the lung of exposed mice. JF - Toxicol Lett Y1 - 2016 A1 - Pascolo, Lorella A1 - Zabucchi, Giuliano A1 - Gianoncelli, Alessandra A1 - Kourousias, George A1 - Trevisan, Elisa A1 - Pascotto, Ernesto A1 - Casarsa, Claudia A1 - Ryan, Chris A1 - Lucattelli, Monica A1 - Lungarella, Giuseppe A1 - Cavarra, Eleonora A1 - Bartalesi, Barbara A1 - Zweyer, Marina A1 - Cammisuli, Francesca A1 - Melato, Mauro A1 - Borelli, Violetta AB -

Human exposure to asbestos can cause a wide variety of lung diseases that are still a current major health concern, even if asbestos has been banned in many countries. It has been shown in many studies that asbestos fibers, ingested by alveolar macrophages, disrupt lung iron homeostasis by sequestering iron. Calcium can also be deposited on the fibers. The pathways along which iron and above all calcium interact with fibers are still unknown. Our aim was that of investigating if the iron accumulation induced by the inhaled asbestos fibers also involves calcium ions accumulation. Lung sections of asbestos-exposed mice were analyzed using an extremely sensitive procedure available at the synchrotron facilities, that provides morphological and chemical information based on X-ray fluorescence microspectroscopy (μ-XRF). In this study we show that (1) where conventional histochemical procedures revealed only weak deposits of iron and calcium, μ-XRF analysis is able to detect significant deposits of both iron and calcium on the inhaled asbestos fibers; (2) the extent of the deposition of these ions is proportionally directly related and (3) iron and calcium deposition on inhaled asbestos fibers is concomitant with the appearance of inflammatory and hyperplastic reactions.

VL - 241 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26602167?dopt=Abstract ER - TY - JOUR T1 - ACTN1-related thrombocytopenia: identification of novel families for phenotypic characterization. JF - Blood Y1 - 2015 A1 - Bottega, Roberta A1 - Marconi, Caterina A1 - Faleschini, Michela A1 - Baj, Gabriele A1 - Cagioni, Claudia A1 - Pecci, Alessandro A1 - Pippucci, Tommaso A1 - Ramenghi, Ugo A1 - Pardini, Simonetta A1 - Ngu, Loretta A1 - Baronci, Carlo A1 - Kunishima, Shinji A1 - Balduini, Carlo L A1 - Seri, Marco A1 - Savoia, Anna A1 - Noris, Patrizia KW - Actinin KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Blood Platelets KW - Case-Control Studies KW - Child KW - Child, Preschool KW - Female KW - Gene Expression KW - Genotype KW - Heterozygote KW - Humans KW - Male KW - Middle Aged KW - Mutation, Missense KW - Pedigree KW - Phenotype KW - Platelet Count KW - Severity of Illness Index KW - Thrombocytopenia KW - Thrombopoiesis KW - Thrombopoietin AB -

Inherited thrombocytopenias (ITs) are a heterogeneous group of syndromic and nonsyndromic diseases caused by mutations affecting different genes. Alterations of ACTN1, the gene encoding for α-actinin 1, have recently been identified in a few families as being responsible for a mild form of IT (ACTN1-related thrombocytopenia; ACTN1-RT). To better characterize this disease, we screened ACTN1 in 128 probands and found 10 (8 novel) missense heterozygous variants in 11 families. Combining bioinformatics, segregation, and functional studies, we demonstrated that all but 1 amino acid substitution had deleterious effects. The clinical and laboratory findings of 31 affected individuals confirmed that ACTN1-RT is a mild macrothrombocytopenia with low risk for bleeding. Low reticulated platelet counts and only slightly increased serum thrombopoietin levels indicated that the latest phases of megakaryopoiesis were affected. Given its relatively high frequency in our cohort (4.2%), ACTN1-RT has to be taken into consideration in the differential diagnosis of ITs.

VL - 125 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25361813?dopt=Abstract ER - TY - JOUR T1 - Advertisements of follow-on formula and their perception by pregnant women and mothers in Italy. JF - Arch Dis Child Y1 - 2015 A1 - Cattaneo, Adriano A1 - Pani, Paola A1 - Carletti, Claudia A1 - Guidetti, Margherita A1 - Mutti, Valentina A1 - Guidetti, Cecilia A1 - Knowles, Alessandra KW - Adult KW - Advertising as Topic KW - Attitude to Health KW - Cross-Sectional Studies KW - Female KW - Humans KW - Infant KW - Infant Formula KW - Italy KW - Mothers KW - Perception KW - Periodicals as Topic KW - Pregnancy KW - Pregnant Women KW - Reading KW - Surveys and Questionnaires KW - Young Adult AB -

OBJECTIVE: To assess how follow-on formula milks for infants aged 6-12 months are presented to and understood by mothers.

DESIGN: A quantitative and qualitative cross-sectional study including (1) an analysis of advertisements in three magazines for parents; (2) in-depth semistructured qualitative interviews to pregnant women on their perception of two advertisements for follow-on formula and (3) self-administered questionnaires for mothers to explore their exposure to and perception of formula advertisements.

PARTICIPANTS: Eighty pregnant women 32-36 weeks of gestation with no previous children and 562 mothers of children <3 years old.

SETTING: Maternal and child health centres in eight cities of Italy.

RESULTS: Advertisements of formula (n=89) represented about 7% of all advertisements in the three magazines, the majority (58%) being for follow-on formula. Advertisements were parent-oriented, aimed at helping parents solve health problems of their babies or at eliciting good feelings, or both. The qualitative interviews to pregnant women showed inability to define the advertised products at first glance due to the ambiguity of the numeral 2 and the presumed age of the portrayed baby; this inability did not disappear after carefully viewing the advertisements and reading the text. When asked in the self-administered questionnaires whether they had ever come across advertisements of infant formula, 81% of mothers reported that they had, despite the legal inexistence of such advertisements, and 65% thought that it was for a product to be used from birth.

CONCLUSIONS: Advertisements of follow-on formula are perceived by pregnant women and mothers as promoting infant formula.

VL - 100 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25512963?dopt=Abstract ER - TY - JOUR T1 - Alendronate, a double-edged sword acting in the mevalonate pathway. JF - Mol Med Rep Y1 - 2015 A1 - Tricarico, Paola Maura A1 - Girardelli, Martina A1 - Kleiner, Giulio A1 - Knowles, Alessandra A1 - Valencic, Erica A1 - Crovella, Sergio A1 - Marcuzzi, Annalisa AB -

Aminobisphosphonate aledronate is a compound commonly used clinically for the treatment of osteoporosis and other bone diseases, as a result of it preventing bone resorption. However, in previous years it has also been used to obtain cellular and animal models of a rare genetic disorder termed Mevalonate Kinase Deficiency (MKD). MKD is caused by mutations affecting the mevalonate kinase enzyme, in the cholesterol pathway and alendronate can be used to biochemically mimic the genetic defect as it inhibits farnesyl pyrophosphate synthase in the same pathway. Despite evidence in favor of the inhibition exerted on the mevalonate pathway, there is at least one clinical case of MKD in which alendronate improved not only skeletal and bone fractures, as expected, but also MKD clinical features. Based on this finding, the present study assessed the anti‑inflammatory properties of this aminobisphosphonate in vitro. No anti‑inflammatory effects of alendronate were observed in the in vitro experiments. Since MKD lacks specific treatments, these results may assist scientists and physicians in making the decision as to the most suitable choice of therapeutic compounds for this neglected disease.

VL - 12 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26096667?dopt=Abstract ER - TY - JOUR T1 - Appendicitis in children less than five years old: A challenge for the general practitioner. JF - World J Clin Pediatr Y1 - 2015 A1 - Marzuillo, Pierluigi A1 - Germani, Claudio A1 - Krauss, Baruch S A1 - Barbi, Egidio AB -

Acute appendicitis is one of the most common indications for abdominal surgery in pediatrics with peak incidence in the second decade of life. Acute appendicitis in the first years of life is an uncommon event. The clinical presentation is often varied and the diagnosis may be overshadowed by other medical conditions. Gastroenteritis is the most common misdiagnosis, with a history of diarrhea present in 33% to 41% of patients. Pain is the most common presenting symptom in children less than 5 years old, followed by vomiting, fever, anorexia and diarrhea. The most common physical sign is focal tenderness (61% of the patients) followed by guarding (55%), diffuse tenderness (39%), rebound (32%), and mass (6%). Neonatal appendicitis is a very rare disease with high mortality; presenting symptoms are nonspecific with abdominal distension representing the main clinical presentation. The younger the patient, the earlier perforation occurs: 70% of patients less than 3 years develop a perforation within 48 h of onset of symptoms. A timely diagnosis reduces the risk of complications. We highlight the epidemiology, pathophysiology, clinical signs and laboratory clues of appendicitis in young children and suggest an algorithm for early diagnosis.

VL - 4 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26015876?dopt=Abstract ER - TY - JOUR T1 - Brain-derived neurotrophic factor serum levels in genetically isolated populations: gender-specific association with anxiety disorder subtypes but not with anxiety levels or Val66Met polymorphism. JF - PeerJ Y1 - 2015 A1 - Carlino, Davide A1 - Francavilla, Ruggiero A1 - Baj, Gabriele A1 - Kulak, Karolina A1 - d'Adamo, Pio A1 - Ulivi, Sheila A1 - Cappellani, Stefania A1 - Gasparini, Paolo A1 - Tongiorgi, Enrico AB -

Anxiety disorders (ADs) are disabling chronic disorders with exaggerated behavioral response to threats. This study was aimed at testing the hypothesis that ADs may be associated with reduced neurotrophic activity, particularly of Brain-derived neurotrophic factor (BDNF), and determining possible effects of genetics on serum BDNF concentrations. In 672 adult subjects from six isolated villages in North-Eastern Italy with high inbreeding, we determined serum BDNF levels and identified subjects with different ADs subtypes such as Social and Specific Phobias (PHSOC, PHSP), Generalized Anxiety Disorder (GAD), and Panic Disorder (PAD). Analysis of the population as a whole or individual village showed no significant correlation between serum BDNF levels and Val66Met polymorphism and no association with anxiety levels. Stratification of subjects highlighted a significant decrease in serum BDNF in females with GAD and males with PHSP. This study indicates low heritability and absence of any impact of the Val66Met polymorphism on circulating concentrations of BDNF. Our results show that BDNF is not a general biomarker of anxiety but serum BDNF levels correlate in a gender-specific manner with ADs subtypes.

VL - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26539329?dopt=Abstract ER - TY - JOUR T1 - Comment on: 'Anthropometric parameters in relation to glycaemic status and lipid profile in a multi-ethnic sample in Italy' by Gualdi-Russo et al. JF - Public Health Nutr Y1 - 2015 A1 - Monasta, Lorenzo A1 - Knowles, Alessandra U1 - http://www.ncbi.nlm.nih.gov/pubmed/26507801?dopt=Abstract ER - TY - JOUR T1 - Directional dominance on stature and cognition in diverse human populations. JF - Nature Y1 - 2015 A1 - Joshi, Peter K A1 - Esko, Tõnu A1 - Mattsson, Hannele A1 - Eklund, Niina A1 - Gandin, Ilaria A1 - Nutile, Teresa A1 - Jackson, Anne U A1 - Schurmann, Claudia A1 - Smith, Albert V A1 - Zhang, Weihua A1 - Okada, Yukinori A1 - Stančáková, Alena A1 - Faul, Jessica D A1 - Zhao, Wei A1 - Bartz, Traci M A1 - Concas, Maria Pina A1 - Franceschini, Nora A1 - Enroth, Stefan A1 - Vitart, Veronique A1 - Trompet, Stella A1 - Guo, Xiuqing A1 - Chasman, Daniel I A1 - O'Connel, Jeffrey R A1 - Corre, Tanguy A1 - Nongmaithem, Suraj S A1 - Chen, Yuning A1 - Mangino, Massimo A1 - Ruggiero, Daniela A1 - Traglia, Michela A1 - Farmaki, Aliki-Eleni A1 - Kacprowski, Tim A1 - Bjonnes, Andrew A1 - van der Spek, Ashley A1 - Wu, Ying A1 - Giri, Anil K A1 - Yanek, Lisa R A1 - Wang, Lihua A1 - Hofer, Edith A1 - Rietveld, Cornelius A A1 - McLeod, Olga A1 - Cornelis, Marilyn C A1 - Pattaro, Cristian A1 - Verweij, Niek A1 - Baumbach, Clemens A1 - Abdellaoui, Abdel A1 - Warren, Helen R A1 - Vuckovic, Dragana A1 - Mei, Hao A1 - Bouchard, Claude A1 - Perry, John R B A1 - Cappellani, Stefania A1 - Mirza, Saira S A1 - Benton, Miles C A1 - Broeckel, Ulrich A1 - Medland, Sarah E A1 - Lind, Penelope A A1 - Malerba, Giovanni A1 - Drong, Alexander A1 - Yengo, Loic A1 - Bielak, Lawrence F A1 - Zhi, Degui A1 - van der Most, Peter J A1 - Shriner, Daniel A1 - Mägi, Reedik A1 - Hemani, Gibran A1 - Karaderi, Tugce A1 - Wang, Zhaoming A1 - Liu, Tian A1 - Demuth, Ilja A1 - Zhao, Jing Hua A1 - Meng, Weihua A1 - Lataniotis, Lazaros A1 - van der Laan, Sander W A1 - Bradfield, Jonathan P A1 - Wood, Andrew R A1 - Bonnefond, Amelie A1 - Ahluwalia, Tarunveer S A1 - Hall, Leanne M A1 - Salvi, Erika A1 - Yazar, Seyhan A1 - Carstensen, Lisbeth A1 - de Haan, Hugoline G A1 - Abney, Mark A1 - Afzal, Uzma A1 - Allison, Matthew A A1 - Amin, Najaf A1 - Asselbergs, Folkert W A1 - Bakker, Stephan J L A1 - Barr, R Graham A1 - Baumeister, Sebastian E A1 - Benjamin, Daniel J A1 - Bergmann, Sven A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Campbell, Archie A1 - Chakravarti, Aravinda A1 - Chan, Yingleong A1 - Chanock, Stephen J A1 - Chen, Constance A1 - Chen, Y-D Ida A1 - Collins, Francis S A1 - Connell, John A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - Smith, George Davey A1 - Davies, Gail A1 - Dörr, Marcus A1 - Ehret, Georg A1 - Ellis, Stephen B A1 - Feenstra, Bjarke A1 - Feitosa, Mary F A1 - Ford, Ian A1 - Fox, Caroline S A1 - Frayling, Timothy M A1 - Friedrich, Nele A1 - Geller, Frank A1 - Scotland, Generation A1 - Gillham-Nasenya, Irina A1 - Gottesman, Omri A1 - Graff, Misa A1 - Grodstein, Francine A1 - Gu, Charles A1 - Haley, Chris A1 - Hammond, Christopher J A1 - Harris, Sarah E A1 - Harris, Tamara B A1 - Hastie, Nicholas D A1 - Heard-Costa, Nancy L A1 - Heikkilä, Kauko A1 - Hocking, Lynne J A1 - Homuth, Georg A1 - Hottenga, Jouke-Jan A1 - Huang, Jinyan A1 - Huffman, Jennifer E A1 - Hysi, Pirro G A1 - Ikram, M Arfan A1 - Ingelsson, Erik A1 - Joensuu, Anni A1 - Johansson, Åsa A1 - Jousilahti, Pekka A1 - Jukema, J Wouter A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kanoni, Stavroula A1 - Kerr, Shona M A1 - Khan, Nazir M A1 - Koellinger, Philipp A1 - Koistinen, Heikki A A1 - Kooner, Manraj K A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Lahti, Jari A1 - Launer, Lenore J A1 - Lea, Rodney A A1 - Lehne, Benjamin A1 - Lehtimäki, Terho A1 - Liewald, David C M A1 - Lind, Lars A1 - Loh, Marie A1 - Lokki, Marja-Liisa A1 - London, Stephanie J A1 - Loomis, Stephanie J A1 - Loukola, Anu A1 - Lu, Yingchang A1 - Lumley, Thomas A1 - Lundqvist, Annamari A1 - Männistö, Satu A1 - Marques-Vidal, Pedro A1 - Masciullo, Corrado A1 - Matchan, Angela A1 - Mathias, Rasika A A1 - Matsuda, Koichi A1 - Meigs, James B A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Menni, Cristina A1 - Mentch, Frank D A1 - Mihailov, Evelin A1 - Milani, Lili A1 - Montasser, May E A1 - Montgomery, Grant W A1 - Morrison, Alanna A1 - Myers, Richard H A1 - Nadukuru, Rajiv A1 - Navarro, Pau A1 - Nelis, Mari A1 - Nieminen, Markku S A1 - Nolte, Ilja M A1 - O'Connor, George T A1 - Ogunniyi, Adesola A1 - Padmanabhan, Sandosh A1 - Palmas, Walter R A1 - Pankow, James S A1 - Patarcic, Inga A1 - Pavani, Francesca A1 - Peyser, Patricia A A1 - Pietilainen, Kirsi A1 - Poulter, Neil A1 - Prokopenko, Inga A1 - Ralhan, Sarju A1 - Redmond, Paul A1 - Rich, Stephen S A1 - Rissanen, Harri A1 - Robino, Antonietta A1 - Rose, Lynda M A1 - Rose, Richard A1 - Sala, Cinzia A1 - Salako, Babatunde A1 - Salomaa, Veikko A1 - Sarin, Antti-Pekka A1 - Saxena, Richa A1 - Schmidt, Helena A1 - Scott, Laura J A1 - Scott, William R A1 - Sennblad, Bengt A1 - Seshadri, Sudha A1 - Sever, Peter A1 - Shrestha, Smeeta A1 - Smith, Blair H A1 - Smith, Jennifer A A1 - Soranzo, Nicole A1 - Sotoodehnia, Nona A1 - Southam, Lorraine A1 - Stanton, Alice V A1 - Stathopoulou, Maria G A1 - Strauch, Konstantin A1 - Strawbridge, Rona J A1 - Suderman, Matthew J A1 - Tandon, Nikhil A1 - Tang, Sian-Tsun A1 - Taylor, Kent D A1 - Tayo, Bamidele O A1 - Töglhofer, Anna Maria A1 - Tomaszewski, Maciej A1 - Tšernikova, Natalia A1 - Tuomilehto, Jaakko A1 - Uitterlinden, André G A1 - Vaidya, Dhananjay A1 - van Hylckama Vlieg, Astrid A1 - van Setten, Jessica A1 - Vasankari, Tuula A1 - Vedantam, Sailaja A1 - Vlachopoulou, Efthymia A1 - Vozzi, Diego A1 - Vuoksimaa, Eero A1 - Waldenberger, Melanie A1 - Ware, Erin B A1 - Wentworth-Shields, William A1 - Whitfield, John B A1 - Wild, Sarah A1 - Willemsen, Gonneke A1 - Yajnik, Chittaranjan S A1 - Yao, Jie A1 - Zaza, Gianluigi A1 - Zhu, Xiaofeng A1 - Salem, Rany M A1 - Melbye, Mads A1 - Bisgaard, Hans A1 - Samani, Nilesh J A1 - Cusi, Daniele A1 - Mackey, David A A1 - Cooper, Richard S A1 - Froguel, Philippe A1 - Pasterkamp, Gerard A1 - Grant, Struan F A A1 - Hakonarson, Hakon A1 - Ferrucci, Luigi A1 - Scott, Robert A A1 - Morris, Andrew D A1 - Palmer, Colin N A A1 - Dedoussis, George A1 - Deloukas, Panos A1 - Bertram, Lars A1 - Lindenberger, Ulman A1 - Berndt, Sonja I A1 - Lindgren, Cecilia M A1 - Timpson, Nicholas J A1 - Tönjes, Anke A1 - Munroe, Patricia B A1 - Sørensen, Thorkild I A A1 - Rotimi, Charles N A1 - Arnett, Donna K A1 - Oldehinkel, Albertine J A1 - Kardia, Sharon L R A1 - Balkau, Beverley A1 - Gambaro, Giovanni A1 - Morris, Andrew P A1 - Eriksson, Johan G A1 - Wright, Margie J A1 - Martin, Nicholas G A1 - Hunt, Steven C A1 - Starr, John M A1 - Deary, Ian J A1 - Griffiths, Lyn R A1 - Tiemeier, Henning A1 - Pirastu, Nicola A1 - Kaprio, Jaakko A1 - Wareham, Nicholas J A1 - Pérusse, Louis A1 - Wilson, James G A1 - Girotto, Giorgia A1 - Caulfield, Mark J A1 - Raitakari, Olli A1 - Boomsma, Dorret I A1 - Gieger, Christian A1 - van der Harst, Pim A1 - Hicks, Andrew A A1 - Kraft, Peter A1 - Sinisalo, Juha A1 - Knekt, Paul A1 - Johannesson, Magnus A1 - Magnusson, Patrik K E A1 - Hamsten, Anders A1 - Schmidt, Reinhold A1 - Borecki, Ingrid B A1 - Vartiainen, Erkki A1 - Becker, Diane M A1 - Bharadwaj, Dwaipayan A1 - Mohlke, Karen L A1 - Boehnke, Michael A1 - van Duijn, Cornelia M A1 - Sanghera, Dharambir K A1 - Teumer, Alexander A1 - Zeggini, Eleftheria A1 - Metspalu, Andres A1 - Gasparini, Paolo A1 - Ulivi, Sheila A1 - Ober, Carole A1 - Toniolo, Daniela A1 - Rudan, Igor A1 - Porteous, David J A1 - Ciullo, Marina A1 - Spector, Tim D A1 - Hayward, Caroline A1 - Dupuis, Josée A1 - Loos, Ruth J F A1 - Wright, Alan F A1 - Chandak, Giriraj R A1 - Vollenweider, Peter A1 - Shuldiner, Alan R A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - Sattar, Naveed A1 - Gyllensten, Ulf A1 - North, Kari E A1 - Pirastu, Mario A1 - Psaty, Bruce M A1 - Weir, David R A1 - Laakso, Markku A1 - Gudnason, Vilmundur A1 - Takahashi, Atsushi A1 - Chambers, John C A1 - Kooner, Jaspal S A1 - Strachan, David P A1 - Campbell, Harry A1 - Hirschhorn, Joel N A1 - Perola, Markus A1 - Polasek, Ozren A1 - Wilson, James F KW - Biological Evolution KW - Blood Pressure KW - Body Height KW - Cholesterol, LDL KW - Cognition KW - Cohort Studies KW - Educational Status KW - Female KW - Forced Expiratory Volume KW - Genome, Human KW - Homozygote KW - Humans KW - Lung Volume Measurements KW - Male KW - Phenotype AB -

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

VL - 523 IS - 7561 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26131930?dopt=Abstract ER - TY - JOUR T1 - Functionalized synchrotron in-line phase-contrast computed tomography: a novel approach for simultaneous quantification of structural alterations and localization of barium-labelled alveolar macrophages within mouse lung samples. JF - J Synchrotron Radiat Y1 - 2015 A1 - Dullin, Christian A1 - dal Monego, Simeone A1 - Larsson, Emanuel A1 - Mohammadi, Sara A1 - Krenkel, Martin A1 - Garrovo, Chiara A1 - Biffi, Stefania A1 - Lorenzon, Andrea A1 - Markus, Andrea A1 - Napp, Joanna A1 - Salditt, Tim A1 - Accardo, Agostino A1 - Alves, Frauke A1 - Tromba, Giuliana KW - Algorithms KW - Allergens KW - Animals KW - Asthma KW - Barium Sulfate KW - Cell Line, Transformed KW - Cell Movement KW - Contrast Media KW - Disease Models, Animal KW - Female KW - Image Processing, Computer-Assisted KW - Imaging, Three-Dimensional KW - Lung KW - Macrophages, Alveolar KW - Mice KW - Mice, Inbred BALB C KW - Microscopy, Fluorescence KW - Ovalbumin KW - Synchrotrons KW - Tomography, X-Ray Computed AB -

Functionalized computed tomography (CT) in combination with labelled cells is virtually non-existent due to the limited sensitivity of X-ray-absorption-based imaging, but would be highly desirable to realise cell tracking studies in entire organisms. In this study we applied in-line free propagation X-ray phase-contrast CT (XPCT) in an allergic asthma mouse model to assess structural changes as well as the biodistribution of barium-labelled macrophages in lung tissue. Alveolar macrophages that were barium-sulfate-loaded and fluorescent-labelled were instilled intratracheally into asthmatic and control mice. Mice were sacrificed after 24 h, lungs were kept in situ, inflated with air and scanned utilizing XPCT at the SYRMEP beamline (Elettra Synchrotron Light Source, Italy). Single-distance phase retrieval was used to generate data sets with ten times greater contrast-to-noise ratio than absorption-based CT (in our setup), thus allowing to depict and quantify structural hallmarks of asthmatic lungs such as reduced air volume, obstruction of airways and increased soft-tissue content. Furthermore, we found a higher concentration as well as a specific accumulation of the barium-labelled macrophages in asthmatic lung tissue. It is believe that XPCT will be beneficial in preclinical asthma research for both the assessment of therapeutic response as well as the analysis of the role of the recruitment of macrophages to inflammatory sites.

VL - 22 IS - Pt 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25537601?dopt=Abstract ER - TY - JOUR T1 - Genetic studies of body mass index yield new insights for obesity biology. JF - Nature Y1 - 2015 A1 - Locke, Adam E A1 - Kahali, Bratati A1 - Berndt, Sonja I A1 - Justice, Anne E A1 - Pers, Tune H A1 - Day, Felix R A1 - Powell, Corey A1 - Vedantam, Sailaja A1 - Buchkovich, Martin L A1 - Yang, Jian A1 - Croteau-Chonka, Damien C A1 - Esko, Tõnu A1 - Fall, Tove A1 - Ferreira, Teresa A1 - Gustafsson, Stefan A1 - Kutalik, Zoltán A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Randall, Joshua C A1 - Winkler, Thomas W A1 - Wood, Andrew R A1 - Workalemahu, Tsegaselassie A1 - Faul, Jessica D A1 - Smith, Jennifer A A1 - Hua Zhao, Jing A1 - Zhao, Wei A1 - Chen, Jin A1 - Fehrmann, Rudolf A1 - Hedman, Åsa K A1 - Karjalainen, Juha A1 - Schmidt, Ellen M A1 - Absher, Devin A1 - Amin, Najaf A1 - Anderson, Denise A1 - Beekman, Marian A1 - Bolton, Jennifer L A1 - Bragg-Gresham, Jennifer L A1 - Buyske, Steven A1 - Demirkan, Ayse A1 - Deng, Guohong A1 - Ehret, Georg B A1 - Feenstra, Bjarke A1 - Feitosa, Mary F A1 - Fischer, Krista A1 - Goel, Anuj A1 - Gong, Jian A1 - Jackson, Anne U A1 - Kanoni, Stavroula A1 - Kleber, Marcus E A1 - Kristiansson, Kati A1 - Lim, Unhee A1 - Lotay, Vaneet A1 - Mangino, Massimo A1 - Mateo Leach, Irene A1 - Medina-Gomez, Carolina A1 - Medland, Sarah E A1 - Nalls, Michael A A1 - Palmer, Cameron D A1 - Pasko, Dorota A1 - Pechlivanis, Sonali A1 - Peters, Marjolein J A1 - Prokopenko, Inga A1 - Shungin, Dmitry A1 - Stančáková, Alena A1 - Strawbridge, Rona J A1 - Ju Sung, Yun A1 - Tanaka, Toshiko A1 - Teumer, Alexander A1 - Trompet, Stella A1 - van der Laan, Sander W A1 - van Setten, Jessica A1 - Van Vliet-Ostaptchouk, Jana V A1 - Wang, Zhaoming A1 - Yengo, Loic A1 - Zhang, Weihua A1 - Isaacs, Aaron A1 - Albrecht, Eva A1 - Arnlöv, Johan A1 - Arscott, Gillian M A1 - Attwood, Antony P A1 - Bandinelli, Stefania A1 - Barrett, Amy A1 - Bas, Isabelita N A1 - Bellis, Claire A1 - Bennett, Amanda J A1 - Berne, Christian A1 - Blagieva, Roza A1 - Blüher, Matthias A1 - Böhringer, Stefan A1 - Bonnycastle, Lori L A1 - Böttcher, Yvonne A1 - Boyd, Heather A A1 - Bruinenberg, Marcel A1 - Caspersen, Ida H A1 - Ida Chen, Yii-Der A1 - Clarke, Robert A1 - Daw, E Warwick A1 - de Craen, Anton J M A1 - Delgado, Graciela A1 - Dimitriou, Maria A1 - Doney, Alex S F A1 - Eklund, Niina A1 - Estrada, Karol A1 - Eury, Elodie A1 - Folkersen, Lasse A1 - Fraser, Ross M A1 - Garcia, Melissa E A1 - Geller, Frank A1 - Giedraitis, Vilmantas A1 - Gigante, Bruna A1 - Go, Alan S A1 - Golay, Alain A1 - Goodall, Alison H A1 - Gordon, Scott D A1 - Gorski, Mathias A1 - Grabe, Hans-Jörgen A1 - Grallert, Harald A1 - Grammer, Tanja B A1 - Gräßler, Jürgen A1 - Grönberg, Henrik A1 - Groves, Christopher J A1 - Gusto, Gaëlle A1 - Haessler, Jeffrey A1 - Hall, Per A1 - Haller, Toomas A1 - Hallmans, Goran A1 - Hartman, Catharina A A1 - Hassinen, Maija A1 - Hayward, Caroline A1 - Heard-Costa, Nancy L A1 - Helmer, Quinta A1 - Hengstenberg, Christian A1 - Holmen, Oddgeir A1 - Hottenga, Jouke-Jan A1 - James, Alan L A1 - Jeff, Janina M A1 - Johansson, Åsa A1 - Jolley, Jennifer A1 - Juliusdottir, Thorhildur A1 - Kinnunen, Leena A1 - Koenig, Wolfgang A1 - Koskenvuo, Markku A1 - Kratzer, Wolfgang A1 - Laitinen, Jaana A1 - Lamina, Claudia A1 - Leander, Karin A1 - Lee, Nanette R A1 - Lichtner, Peter A1 - Lind, Lars A1 - Lindström, Jaana A1 - Sin Lo, Ken A1 - Lobbens, Stéphane A1 - Lorbeer, Roberto A1 - Lu, Yingchang A1 - Mach, François A1 - Magnusson, Patrik K E A1 - Mahajan, Anubha A1 - McArdle, Wendy L A1 - McLachlan, Stela A1 - Menni, Cristina A1 - Merger, Sigrun A1 - Mihailov, Evelin A1 - Milani, Lili A1 - Moayyeri, Alireza A1 - Monda, Keri L A1 - Morken, Mario A A1 - Mulas, Antonella A1 - Müller, Gabriele A1 - Müller-Nurasyid, Martina A1 - Musk, Arthur W A1 - Nagaraja, Ramaiah A1 - Nöthen, Markus M A1 - Nolte, Ilja M A1 - Pilz, Stefan A1 - Rayner, Nigel W A1 - Renstrom, Frida A1 - Rettig, Rainer A1 - Ried, Janina S A1 - Ripke, Stephan A1 - Robertson, Neil R A1 - Rose, Lynda M A1 - Sanna, Serena A1 - Scharnagl, Hubert A1 - Scholtens, Salome A1 - Schumacher, Fredrick R A1 - Scott, William R A1 - Seufferlein, Thomas A1 - Shi, Jianxin A1 - Vernon Smith, Albert A1 - Smolonska, Joanna A1 - Stanton, Alice V A1 - Steinthorsdottir, Valgerdur A1 - Stirrups, Kathleen A1 - Stringham, Heather M A1 - Sundström, Johan A1 - Swertz, Morris A A1 - Swift, Amy J A1 - Syvänen, Ann-Christine A1 - Tan, Sian-Tsung A1 - Tayo, Bamidele O A1 - Thorand, Barbara A1 - Thorleifsson, Gudmar A1 - Tyrer, Jonathan P A1 - Uh, Hae-Won A1 - Vandenput, Liesbeth A1 - Verhulst, Frank C A1 - Vermeulen, Sita H A1 - Verweij, Niek A1 - Vonk, Judith M A1 - Waite, Lindsay L A1 - Warren, Helen R A1 - Waterworth, Dawn A1 - Weedon, Michael N A1 - Wilkens, Lynne R A1 - Willenborg, Christina A1 - Wilsgaard, Tom A1 - Wojczynski, Mary K A1 - Wong, Andrew A1 - Wright, Alan F A1 - Zhang, Qunyuan A1 - Brennan, Eoin P A1 - Choi, Murim A1 - Dastani, Zari A1 - Drong, Alexander W A1 - Eriksson, Per A1 - Franco-Cereceda, Anders A1 - Gådin, Jesper R A1 - Gharavi, Ali G A1 - Goddard, Michael E A1 - Handsaker, Robert E A1 - Huang, Jinyan A1 - Karpe, Fredrik A1 - Kathiresan, Sekar A1 - Keildson, Sarah A1 - Kiryluk, Krzysztof A1 - Kubo, Michiaki A1 - Lee, Jong-Young A1 - Liang, Liming A1 - Lifton, Richard P A1 - Ma, Baoshan A1 - McCarroll, Steven A A1 - McKnight, Amy J A1 - Min, Josine L A1 - Moffatt, Miriam F A1 - Montgomery, Grant W A1 - Murabito, Joanne M A1 - Nicholson, George A1 - Nyholt, Dale R A1 - Okada, Yukinori A1 - Perry, John R B A1 - Dorajoo, Rajkumar A1 - Reinmaa, Eva A1 - Salem, Rany M A1 - Sandholm, Niina A1 - Scott, Robert A A1 - Stolk, Lisette A1 - Takahashi, Atsushi A1 - Tanaka, Toshihiro A1 - Van't Hooft, Ferdinand M A1 - Vinkhuyzen, Anna A E A1 - Westra, Harm-Jan A1 - Zheng, Wei A1 - Zondervan, Krina T A1 - Heath, Andrew C A1 - Arveiler, Dominique A1 - Bakker, Stephan J L A1 - Beilby, John A1 - Bergman, Richard N A1 - Blangero, John A1 - Bovet, Pascal A1 - Campbell, Harry A1 - Caulfield, Mark J A1 - Cesana, Giancarlo A1 - Chakravarti, Aravinda A1 - Chasman, Daniel I A1 - Chines, Peter S A1 - Collins, Francis S A1 - Crawford, Dana C A1 - Cupples, L Adrienne A1 - Cusi, Daniele A1 - Danesh, John A1 - de Faire, Ulf A1 - den Ruijter, Hester M A1 - Dominiczak, Anna F A1 - Erbel, Raimund A1 - Erdmann, Jeanette A1 - Eriksson, Johan G A1 - Farrall, Martin A1 - Felix, Stephan B A1 - Ferrannini, Ele A1 - Ferrières, Jean A1 - Ford, Ian A1 - Forouhi, Nita G A1 - Forrester, Terrence A1 - Franco, Oscar H A1 - Gansevoort, Ron T A1 - Gejman, Pablo V A1 - Gieger, Christian A1 - Gottesman, Omri A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Hall, Alistair S A1 - Harris, Tamara B A1 - Hattersley, Andrew T A1 - Hicks, Andrew A A1 - Hindorff, Lucia A A1 - Hingorani, Aroon D A1 - Hofman, Albert A1 - Homuth, Georg A1 - Hovingh, G Kees A1 - Humphries, Steve E A1 - Hunt, Steven C A1 - Hyppönen, Elina A1 - Illig, Thomas A1 - Jacobs, Kevin B A1 - Järvelin, Marjo-Riitta A1 - Jöckel, Karl-Heinz A1 - Johansen, Berit A1 - Jousilahti, Pekka A1 - Jukema, J Wouter A1 - Jula, Antti M A1 - Kaprio, Jaakko A1 - Kastelein, John J P A1 - Keinanen-Kiukaanniemi, Sirkka M A1 - Kiemeney, Lambertus A A1 - Knekt, Paul A1 - Kooner, Jaspal S A1 - Kooperberg, Charles A1 - Kovacs, Peter A1 - Kraja, Aldi T A1 - Kumari, Meena A1 - Kuusisto, Johanna A1 - Lakka, Timo A A1 - Langenberg, Claudia A1 - Le Marchand, Loic A1 - Lehtimäki, Terho A1 - Lyssenko, Valeriya A1 - Männistö, Satu A1 - Marette, André A1 - Matise, Tara C A1 - McKenzie, Colin A A1 - McKnight, Barbara A1 - Moll, Frans L A1 - Morris, Andrew D A1 - Morris, Andrew P A1 - Murray, Jeffrey C A1 - Nelis, Mari A1 - Ohlsson, Claes A1 - Oldehinkel, Albertine J A1 - Ong, Ken K A1 - Madden, Pamela A F A1 - Pasterkamp, Gerard A1 - Peden, John F A1 - Peters, Annette A1 - Postma, Dirkje S A1 - Pramstaller, Peter P A1 - Price, Jackie F A1 - Qi, Lu A1 - Raitakari, Olli T A1 - Rankinen, Tuomo A1 - Rao, D C A1 - Rice, Treva K A1 - Ridker, Paul M A1 - Rioux, John D A1 - Ritchie, Marylyn D A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Saramies, Jouko A1 - Sarzynski, Mark A A1 - Schunkert, Heribert A1 - Schwarz, Peter E H A1 - Sever, Peter A1 - Shuldiner, Alan R A1 - Sinisalo, Juha A1 - Stolk, Ronald P A1 - Strauch, Konstantin A1 - Tönjes, Anke A1 - Trégouët, David-Alexandre A1 - Tremblay, Angelo A1 - Tremoli, Elena A1 - Virtamo, Jarmo A1 - Vohl, Marie-Claude A1 - Völker, Uwe A1 - Waeber, Gerard A1 - Willemsen, Gonneke A1 - Witteman, Jacqueline C A1 - Zillikens, M Carola A1 - Adair, Linda S A1 - Amouyel, Philippe A1 - Asselbergs, Folkert W A1 - Assimes, Themistocles L A1 - Bochud, Murielle A1 - Boehm, Bernhard O A1 - Boerwinkle, Eric A1 - Bornstein, Stefan R A1 - Bottinger, Erwin P A1 - Bouchard, Claude A1 - Cauchi, Stéphane A1 - Chambers, John C A1 - Chanock, Stephen J A1 - Cooper, Richard S A1 - de Bakker, Paul I W A1 - Dedoussis, George A1 - Ferrucci, Luigi A1 - Franks, Paul W A1 - Froguel, Philippe A1 - Groop, Leif C A1 - Haiman, Christopher A A1 - Hamsten, Anders A1 - Hui, Jennie A1 - Hunter, David J A1 - Hveem, Kristian A1 - Kaplan, Robert C A1 - Kivimaki, Mika A1 - Kuh, Diana A1 - Laakso, Markku A1 - Liu, Yongmei A1 - Martin, Nicholas G A1 - März, Winfried A1 - Melbye, Mads A1 - Metspalu, Andres A1 - Moebus, Susanne A1 - Munroe, Patricia B A1 - Njølstad, Inger A1 - Oostra, Ben A A1 - Palmer, Colin N A A1 - Pedersen, Nancy L A1 - Perola, Markus A1 - Pérusse, Louis A1 - Peters, Ulrike A1 - Power, Chris A1 - Quertermous, Thomas A1 - Rauramaa, Rainer A1 - Rivadeneira, Fernando A1 - Saaristo, Timo E A1 - Saleheen, Danish A1 - Sattar, Naveed A1 - Schadt, Eric E A1 - Schlessinger, David A1 - Slagboom, P Eline A1 - Snieder, Harold A1 - Spector, Tim D A1 - Thorsteinsdottir, Unnur A1 - Stumvoll, Michael A1 - Tuomilehto, Jaakko A1 - Uitterlinden, André G A1 - Uusitupa, Matti A1 - van der Harst, Pim A1 - Walker, Mark A1 - Wallaschofski, Henri A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wichmann, H-Erich A1 - Wilson, James F A1 - Zanen, Pieter A1 - Borecki, Ingrid B A1 - Deloukas, Panos A1 - Fox, Caroline S A1 - Heid, Iris M A1 - O'Connell, Jeffrey R A1 - Strachan, David P A1 - Stefansson, Kari A1 - van Duijn, Cornelia M A1 - Abecasis, Goncalo R A1 - Franke, Lude A1 - Frayling, Timothy M A1 - McCarthy, Mark I A1 - Visscher, Peter M A1 - Scherag, André A1 - Willer, Cristen J A1 - Boehnke, Michael A1 - Mohlke, Karen L A1 - Lindgren, Cecilia M A1 - Beckmann, Jacques S A1 - Barroso, Inês A1 - North, Kari E A1 - Ingelsson, Erik A1 - Hirschhorn, Joel N A1 - Loos, Ruth J F A1 - Speliotes, Elizabeth K KW - Adipogenesis KW - Adiposity KW - Age Factors KW - Body Mass Index KW - Continental Population Groups KW - Energy Metabolism KW - Europe KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glutamic Acid KW - Humans KW - Insulin KW - Male KW - Obesity KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Synapses AB -

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

VL - 518 IS - 7538 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25673413?dopt=Abstract ER - TY - JOUR T1 - Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers. JF - Nat Genet Y1 - 2015 A1 - Sidore, Carlo A1 - Busonero, Fabio A1 - Maschio, Andrea A1 - Porcu, Eleonora A1 - Naitza, Silvia A1 - Zoledziewska, Magdalena A1 - Mulas, Antonella A1 - Pistis, Giorgio A1 - Steri, Maristella A1 - Danjou, Fabrice A1 - Kwong, Alan A1 - Ortega Del Vecchyo, Vicente Diego A1 - Chiang, Charleston W K A1 - Bragg-Gresham, Jennifer A1 - Pitzalis, Maristella A1 - Nagaraja, Ramaiah A1 - Tarrier, Brendan A1 - Brennan, Christine A1 - Uzzau, Sergio A1 - Fuchsberger, Christian A1 - Atzeni, Rossano A1 - Reinier, Frederic A1 - Berutti, Riccardo A1 - Huang, Jie A1 - Timpson, Nicholas J A1 - Toniolo, Daniela A1 - Gasparini, Paolo A1 - Malerba, Giovanni A1 - Dedoussis, George A1 - Zeggini, Eleftheria A1 - Soranzo, Nicole A1 - Jones, Chris A1 - Lyons, Robert A1 - Angius, Andrea A1 - Kang, Hyun M A1 - Novembre, John A1 - Sanna, Serena A1 - Schlessinger, David A1 - Cucca, Francesco A1 - Abecasis, Goncalo R AB -

We report ∼17.6 million genetic variants from whole-genome sequencing of 2,120 Sardinians; 22% are absent from previous sequencing-based compilations and are enriched for predicted functional consequences. Furthermore, ∼76,000 variants common in our sample (frequency >5%) are rare elsewhere (<0.5% in the 1000 Genomes Project). We assessed the impact of these variants on circulating lipid levels and five inflammatory biomarkers. We observe 14 signals, including 2 major new loci, for lipid levels and 19 signals, including 2 new loci, for inflammatory markers. The new associations would have been missed in analyses based on 1000 Genomes Project data, underlining the advantages of large-scale sequencing in this founder population.

VL - 47 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26366554?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association analysis on five isolated populations identifies variants of the HLA-DOA gene associated with white wine liking. JF - Eur J Hum Genet Y1 - 2015 A1 - Pirastu, Nicola A1 - Kooyman, Maarten A1 - Traglia, Michela A1 - Robino, Antonietta A1 - Willems, Sara M A1 - Pistis, Giorgio A1 - Amin, Najaf A1 - Sala, Cinzia A1 - Karssen, Lennart C A1 - van Duijn, Cornelia M A1 - Toniolo, Daniela A1 - Gasparini, Paolo AB -

Wine is the most popular alcoholic beverage around the world and because of its importance in society has been widely studied. Understanding what drives its flavor has been a quest for decades but much is still unknown and will be determined at least in part by individual taste preferences. Recently studies in the genetics of taste have uncovered the role of different genes in the determination of food preferences giving new insight on its physiology. In this context we have performed a genome-wide association study on red and white wine liking using three isolated populations collected in Italy, and replicated our results on two additional populations coming from the Netherland and Central Asia for a total of 3885 samples. We have found a significant association (P=2.1 × 10(-8)) between white wine liking and rs9276975:C>T a polymorphism in the HLA-DOA gene encoding a non-canonical MHC II molecule, which regulates other MHC II molecules. The same association was also found with red wine liking (P=8.3 × 10(-6)). Sex-separated analysis have also revealed that the effect of HLA-DOA is twice as large in women as compared to men suggesting an interaction between this polymorphism and gender. Our results are one of the first examples of genome-wide association between liking of a commonly consumed food and gene variants. Moreover, our results suggest a role of the MHC system in the determination of food preferences opening new insight in this field in general.

VL - 23 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25758996?dopt=Abstract ER - TY - JOUR T1 - Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. JF - Nat Genet Y1 - 2015 A1 - Noetzli, Leila A1 - Lo, Richard W A1 - Lee-Sherick, Alisa B A1 - Callaghan, Michael A1 - Noris, Patrizia A1 - Savoia, Anna A1 - Rajpurkar, Madhvi A1 - Jones, Kenneth A1 - Gowan, Katherine A1 - Balduini, Carlo L A1 - Pecci, Alessandro A1 - Gnan, Chiara A1 - De Rocco, Daniela A1 - Doubek, Michael A1 - Li, Ling A1 - Lu, Lily A1 - Leung, Richard A1 - Landolt-Marticorena, Carolina A1 - Hunger, Stephen A1 - Heller, Paula A1 - Gutierrez-Hartmann, Arthur A1 - Xiayuan, Liang A1 - Pluthero, Fred G A1 - Rowley, Jesse W A1 - Weyrich, Andrew S A1 - Kahr, Walter H A A1 - Porter, Christopher C A1 - Di Paola, Jorge KW - Adult KW - Child, Preschool KW - DNA Mutational Analysis KW - Erythrocytes, Abnormal KW - Exome KW - Female KW - Genetic Association Studies KW - Genetic Predisposition to Disease KW - Germ-Line Mutation KW - HEK293 Cells KW - Hematologic Diseases KW - Humans KW - Male KW - Mutation, Missense KW - Pedigree KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma KW - Proto-Oncogene Proteins c-ets KW - Repressor Proteins KW - Thrombocytopenia AB -

Some familial platelet disorders are associated with predisposition to leukemia, myelodysplastic syndrome (MDS) or dyserythropoietic anemia. We identified a family with autosomal dominant thrombocytopenia, high erythrocyte mean corpuscular volume (MCV) and two occurrences of B cell-precursor acute lymphoblastic leukemia (ALL). Whole-exome sequencing identified a heterozygous single-nucleotide change in ETV6 (ets variant 6), c.641C>T, encoding a p.Pro214Leu substitution in the central domain, segregating with thrombocytopenia and elevated MCV. A screen of 23 families with similar phenotypes identified 2 with ETV6 mutations. One family also had a mutation encoding p.Pro214Leu and one individual with ALL. The other family had a c.1252A>G transition producing a p.Arg418Gly substitution in the DNA-binding domain, with alternative splicing and exon skipping. Functional characterization of these mutations showed aberrant cellular localization of mutant and endogenous ETV6, decreased transcriptional repression and altered megakaryocyte maturation. Our findings underscore a key role for ETV6 in platelet formation and leukemia predisposition.

VL - 47 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25807284?dopt=Abstract ER - TY - JOUR T1 - The Global Burden of Cancer 2013. JF - JAMA Oncol Y1 - 2015 A1 - Fitzmaurice, Christina A1 - Dicker, Daniel A1 - Pain, Amanda A1 - Hamavid, Hannah A1 - Moradi-Lakeh, Maziar A1 - MacIntyre, Michael F A1 - Allen, Christine A1 - Hansen, Gillian A1 - Woodbrook, Rachel A1 - Wolfe, Charles A1 - Hamadeh, Randah R A1 - Moore, Ami A1 - Werdecker, Andrea A1 - Gessner, Bradford D A1 - Te Ao, Braden A1 - McMahon, Brian A1 - Karimkhani, Chante A1 - Yu, Chuanhua A1 - Cooke, Graham S A1 - Schwebel, David C A1 - Carpenter, David O A1 - Pereira, David M A1 - Nash, Denis A1 - Kazi, Dhruv S A1 - De Leo, Diego A1 - Plass, Dietrich A1 - Ukwaja, Kingsley N A1 - Thurston, George D A1 - Yun Jin, Kim A1 - Simard, Edgar P A1 - Mills, Edward A1 - Park, Eun-Kee A1 - Catalá-López, Ferrán A1 - deVeber, Gabrielle A1 - Gotay, Carolyn A1 - Khan, Gulfaraz A1 - Hosgood, H Dean A1 - Santos, Itamar S A1 - Leasher, Janet L A1 - Singh, Jasvinder A1 - Leigh, James A1 - Jonas, Jost A1 - Sanabria, Juan A1 - Beardsley, Justin A1 - Jacobsen, Kathryn H A1 - Takahashi, Ken A1 - Franklin, Richard C A1 - Ronfani, Luca A1 - Montico, Marcella A1 - Naldi, Luigi A1 - Tonelli, Marcello A1 - Geleijnse, Johanna A1 - Petzold, Max A1 - Shrime, Mark G A1 - Younis, Mustafa A1 - Yonemoto, Naohiro A1 - Breitborde, Nicholas A1 - Yip, Paul A1 - Pourmalek, Farshad A1 - Lotufo, Paulo A A1 - Esteghamati, Alireza A1 - Hankey, Graeme J A1 - Ali, Raghib A1 - Lunevicius, Raimundas A1 - Malekzadeh, Reza A1 - Dellavalle, Robert A1 - Weintraub, Robert A1 - Lucas, Robyn A1 - Hay, Roderick A1 - Rojas-Rueda, David A1 - Westerman, Ronny A1 - Sepanlou, Sadaf G A1 - Nolte, Sandra A1 - Patten, Scott A1 - Weichenthal, Scott A1 - Abera, Semaw Ferede A1 - Fereshtehnejad, Seyed-Mohammad A1 - Shiue, Ivy A1 - Driscoll, Tim A1 - Vasankari, Tommi A1 - Alsharif, Ubai A1 - Rahimi-Movaghar, Vafa A1 - Vlassov, Vasiliy V A1 - Marcenes, W S A1 - Mekonnen, Wubegzier A1 - Melaku, Yohannes Adama A1 - Yano, Yuichiro A1 - Artaman, Al A1 - Campos, Ismael A1 - MacLachlan, Jennifer A1 - Mueller, Ulrich A1 - Kim, Daniel A1 - Trillini, Matias A1 - Eshrati, Babak A1 - Williams, Hywel C A1 - Shibuya, Kenji A1 - Dandona, Rakhi A1 - Murthy, Kinnari A1 - Cowie, Benjamin A1 - Amare, Azmeraw T A1 - Antonio, Carl Abelardo A1 - Castañeda-Orjuela, Carlos A1 - van Gool, Coen H A1 - Violante, Francesco A1 - Oh, In-Hwan A1 - Deribe, Kedede A1 - Soreide, Kjetil A1 - Knibbs, Luke A1 - Kereselidze, Maia A1 - Green, Mark A1 - Cárdenas, Rosario A1 - Roy, Nobhojit A1 - Tillman, Taavi A1 - Li, Yongmei A1 - Krueger, Hans A1 - Monasta, Lorenzo A1 - Dey, Subhojit A1 - Sheikhbahaei, Sara A1 - Hafezi-Nejad, Nima A1 - Kumar, G Anil A1 - Sreeramareddy, Chandrashekhar T A1 - Dandona, Lalit A1 - Wang, Haidong A1 - Vollset, Stein Emil A1 - Mokdad, Ali A1 - Salomon, Joshua A A1 - Lozano, Rafael A1 - Vos, Theo A1 - Forouzanfar, Mohammad A1 - Lopez, Alan A1 - Murray, Christopher A1 - Naghavi, Mohsen AB -

IMPORTANCE: Cancer is among the leading causes of death worldwide. Current estimates of cancer burden in individual countries and regions are necessary to inform local cancer control strategies.

OBJECTIVE: To estimate mortality, incidence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 28 cancers in 188 countries by sex from 1990 to 2013.

EVIDENCE REVIEW: The general methodology of the Global Burden of Disease (GBD) 2013 study was used. Cancer registries were the source for cancer incidence data as well as mortality incidence (MI) ratios. Sources for cause of death data include vital registration system data, verbal autopsy studies, and other sources. The MI ratios were used to transform incidence data to mortality estimates and cause of death estimates to incidence estimates. Cancer prevalence was estimated using MI ratios as surrogates for survival data; YLDs were calculated by multiplying prevalence estimates with disability weights, which were derived from population-based surveys; YLLs were computed by multiplying the number of estimated cancer deaths at each age with a reference life expectancy; and DALYs were calculated as the sum of YLDs and YLLs.

FINDINGS: In 2013 there were 14.9 million incident cancer cases, 8.2 million deaths, and 196.3 million DALYs. Prostate cancer was the leading cause for cancer incidence (1.4 million) for men and breast cancer for women (1.8 million). Tracheal, bronchus, and lung (TBL) cancer was the leading cause for cancer death in men and women, with 1.6 million deaths. For men, TBL cancer was the leading cause of DALYs (24.9 million). For women, breast cancer was the leading cause of DALYs (13.1 million). Age-standardized incidence rates (ASIRs) per 100 000 and age-standardized death rates (ASDRs) per 100 000 for both sexes in 2013 were higher in developing vs developed countries for stomach cancer (ASIR, 17 vs 14; ASDR, 15 vs 11), liver cancer (ASIR, 15 vs 7; ASDR, 16 vs 7), esophageal cancer (ASIR, 9 vs 4; ASDR, 9 vs 4), cervical cancer (ASIR, 8 vs 5; ASDR, 4 vs 2), lip and oral cavity cancer (ASIR, 7 vs 6; ASDR, 2 vs 2), and nasopharyngeal cancer (ASIR, 1.5 vs 0.4; ASDR, 1.2 vs 0.3). Between 1990 and 2013, ASIRs for all cancers combined (except nonmelanoma skin cancer and Kaposi sarcoma) increased by more than 10% in 113 countries and decreased by more than 10% in 12 of 188 countries.

CONCLUSIONS AND RELEVANCE: Cancer poses a major threat to public health worldwide, and incidence rates have increased in most countries since 1990. The trend is a particular threat to developing nations with health systems that are ill-equipped to deal with complex and expensive cancer treatments. The annual update on the Global Burden of Cancer will provide all stakeholders with timely estimates to guide policy efforts in cancer prevention, screening, treatment, and palliation.

VL - 1 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26181261?dopt=Abstract ER - TY - JOUR T1 - Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. JF - Lancet Y1 - 2015 A1 - Forouzanfar, Mohammad H A1 - Alexander, Lily A1 - Anderson, H Ross A1 - Bachman, Victoria F A1 - Biryukov, Stan A1 - Brauer, Michael A1 - Burnett, Richard A1 - Casey, Daniel A1 - Coates, Matthew M A1 - Cohen, Aaron A1 - Delwiche, Kristen A1 - Estep, Kara A1 - Frostad, Joseph J A1 - Astha, K C A1 - Kyu, Hmwe H A1 - Moradi-Lakeh, Maziar A1 - Ng, Marie A1 - Slepak, Erica Leigh A1 - Thomas, Bernadette A A1 - Wagner, Joseph A1 - Aasvang, Gunn Marit A1 - Abbafati, Cristiana A1 - Abbasoglu Ozgoren, Ayse A1 - Abd-Allah, Foad A1 - Abera, Semaw F A1 - Aboyans, Victor A1 - Abraham, Biju A1 - Abraham, Jerry Puthenpurakal A1 - Abubakar, Ibrahim A1 - Abu-Rmeileh, Niveen M E A1 - Aburto, Tania C A1 - Achoki, Tom A1 - Adelekan, Ademola A1 - Adofo, Koranteng A1 - Adou, Arsène K A1 - Adsuar, José C A1 - Afshin, Ashkan A1 - Agardh, Emilie E A1 - Al Khabouri, Mazin J A1 - Al Lami, Faris H A1 - Alam, Sayed Saidul A1 - Alasfoor, Deena A1 - Albittar, Mohammed I A1 - Alegretti, Miguel A A1 - Aleman, Alicia V A1 - Alemu, Zewdie A A1 - Alfonso-Cristancho, Rafael A1 - Alhabib, Samia A1 - Ali, Raghib A1 - Ali, Mohammed K A1 - Alla, François A1 - Allebeck, Peter A1 - Allen, Peter J A1 - Alsharif, Ubai A1 - Alvarez, Elena A1 - Alvis-Guzmán, Nelson A1 - Amankwaa, Adansi A A1 - Amare, Azmeraw T A1 - Ameh, Emmanuel A A1 - Ameli, Omid A1 - Amini, Heresh A1 - Ammar, Walid A1 - Anderson, Benjamin O A1 - Antonio, Carl Abelardo T A1 - Anwari, Palwasha A1 - Argeseanu Cunningham, Solveig A1 - Arnlöv, Johan A1 - Arsenijevic, Valentina S Arsic A1 - Artaman, Al A1 - Asghar, Rana J A1 - Assadi, Reza A1 - Atkins, Lydia S A1 - Atkinson, Charles A1 - Avila, Marco A A1 - Awuah, Baffour A1 - Badawi, Alaa A1 - Bahit, Maria C A1 - Bakfalouni, Talal A1 - Balakrishnan, Kalpana A1 - Balalla, Shivanthi A1 - Balu, Ravi Kumar A1 - Banerjee, Amitava A1 - Barber, Ryan M A1 - Barker-Collo, Suzanne L A1 - Barquera, Simon A1 - Barregard, Lars A1 - Barrero, Lope H A1 - Barrientos-Gutierrez, Tonatiuh A1 - Basto-Abreu, Ana C A1 - Basu, Arindam A1 - Basu, Sanjay A1 - Basulaiman, Mohammed O A1 - Batis Ruvalcaba, Carolina A1 - Beardsley, Justin A1 - Bedi, Neeraj A1 - Bekele, Tolesa A1 - Bell, Michelle L A1 - Benjet, Corina A1 - Bennett, Derrick A A1 - Benzian, Habib A1 - Bernabe, Eduardo A1 - Beyene, Tariku J A1 - Bhala, Neeraj A1 - Bhalla, Ashish A1 - Bhutta, Zulfiqar A A1 - Bikbov, Boris A1 - Bin Abdulhak, Aref A A1 - Blore, Jed D A1 - Blyth, Fiona M A1 - Bohensky, Megan A A1 - Bora Başara, Berrak A1 - Borges, Guilherme A1 - Bornstein, Natan M A1 - Bose, Dipan A1 - Boufous, Soufiane A1 - Bourne, Rupert R A1 - Brainin, Michael A1 - Brazinova, Alexandra A1 - Breitborde, Nicholas J A1 - Brenner, Hermann A1 - Briggs, Adam D M A1 - Broday, David M A1 - Brooks, Peter M A1 - Bruce, Nigel G A1 - Brugha, Traolach S A1 - Brunekreef, Bert A1 - Buchbinder, Rachelle A1 - Bui, Linh N A1 - Bukhman, Gene A1 - Bulloch, Andrew G A1 - Burch, Michael A1 - Burney, Peter G J A1 - Campos-Nonato, Ismael R A1 - Campuzano, Julio C A1 - Cantoral, Alejandra J A1 - 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BACKGROUND: The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution.

METHODS: Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk-outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990-2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian meta-regression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol.

FINDINGS: All risks combined account for 57·2% (95% uncertainty interval [UI] 55·8-58·5) of deaths and 41·6% (40·1-43·0) of DALYs. Risks quantified account for 87·9% (86·5-89·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 million deaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs, child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 million deaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for 4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa.

INTERPRETATION: Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks.

FUNDING: Bill & Melinda Gates Foundation.

VL - 386 IS - 10010 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26364544?dopt=Abstract ER - TY - JOUR T1 - Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013: quantifying the epidemiological transition. JF - Lancet Y1 - 2015 A1 - Murray, Christopher J L A1 - Barber, Ryan M A1 - Foreman, Kyle J A1 - Abbasoglu Ozgoren, Ayse A1 - Abd-Allah, Foad A1 - Abera, Semaw F A1 - Aboyans, Victor A1 - Abraham, Jerry P A1 - Abubakar, Ibrahim A1 - Abu-Raddad, Laith J A1 - Abu-Rmeileh, Niveen M A1 - Achoki, Tom A1 - Ackerman, Ilana N A1 - Ademi, Zanfina A1 - Adou, Arsène K A1 - Adsuar, José C A1 - Afshin, Ashkan A1 - Agardh, Emilie E A1 - Alam, Sayed Saidul A1 - Alasfoor, Deena A1 - Albittar, Mohammed I A1 - Alegretti, Miguel A A1 - Alemu, Zewdie A A1 - Alfonso-Cristancho, Rafael A1 - Alhabib, Samia A1 - Ali, Raghib A1 - Alla, François A1 - Allebeck, Peter A1 - AlMazroa, Mohammad A A1 - Alsharif, Ubai A1 - Alvarez, Elena A1 - Alvis-Guzmán, Nelson A1 - Amare, Azmeraw T A1 - Ameh, Emmanuel A A1 - Amini, Heresh A1 - Ammar, Walid A1 - Anderson, H Ross A1 - Anderson, Benjamin O A1 - Antonio, Carl Abelardo T A1 - Anwari, Palwasha A1 - Arnlöv, Johan A1 - Arsic Arsenijevic, Valentina S A1 - Artaman, Al A1 - Asghar, Rana J A1 - Assadi, Reza A1 - Atkins, Lydia S A1 - Avila, Marco A A1 - Awuah, Baffour A1 - Bachman, Victoria F A1 - Badawi, Alaa A1 - Bahit, Maria C A1 - Balakrishnan, Kalpana A1 - Banerjee, Amitava A1 - Barker-Collo, Suzanne L A1 - Barquera, Simon A1 - Barregard, Lars A1 - Barrero, Lope H A1 - Basu, Arindam A1 - Basu, Sanjay A1 - Basulaiman, Mohammed O A1 - Beardsley, Justin A1 - Bedi, Neeraj A1 - Beghi, Ettore A1 - Bekele, Tolesa A1 - Bell, Michelle L A1 - Benjet, Corina A1 - Bennett, Derrick A A1 - Bensenor, Isabela M A1 - Benzian, Habib A1 - Bernabe, Eduardo A1 - Bertozzi-Villa, Amelia A1 - Beyene, Tariku J A1 - Bhala, Neeraj A1 - Bhalla, Ashish A1 - Bhutta, Zulfiqar A A1 - Bienhoff, Kelly A1 - Bikbov, Boris A1 - Biryukov, Stan A1 - Blore, Jed D A1 - Blosser, Christopher D A1 - Blyth, Fiona M A1 - Bohensky, Megan A A1 - Bolliger, Ian W A1 - Bora Başara, Berrak A1 - Bornstein, Natan M A1 - Bose, Dipan A1 - Boufous, Soufiane A1 - Bourne, Rupert R A A1 - Boyers, Lindsay N A1 - Brainin, Michael A1 - Brayne, Carol E A1 - Brazinova, Alexandra A1 - Breitborde, Nicholas J K A1 - Brenner, Hermann A1 - Briggs, Adam D A1 - Brooks, Peter M A1 - Brown, Jonathan C A1 - Brugha, Traolach S A1 - Buchbinder, Rachelle A1 - Buckle, Geoffrey C A1 - Budke, Christine M A1 - Bulchis, Anne A1 - Bulloch, Andrew G A1 - Campos-Nonato, Ismael R A1 - Carabin, Hélène A1 - Carapetis, Jonathan R A1 - Cárdenas, Rosario A1 - Carpenter, David O A1 - Caso, Valeria A1 - Castañeda-Orjuela, Carlos A A1 - Castro, Ruben E A1 - Catalá-López, Ferrán A1 - Cavalleri, Fiorella A1 - Cavlin, Alanur A1 - Chadha, Vineet K A1 - Chang, Jung-Chen A1 - Charlson, Fiona J A1 - Chen, Honglei A1 - Chen, Wanqing A1 - Chiang, Peggy P A1 - Chimed-Ochir, Odgerel A1 - Chowdhury, Rajiv A1 - Christensen, Hanne A1 - Christophi, Costas A A1 - Cirillo, Massimo A1 - Coates, Matthew M A1 - Coffeng, Luc E A1 - Coggeshall, Megan S A1 - Colistro, Valentina A1 - Colquhoun, Samantha M A1 - Cooke, Graham S A1 - Cooper, Cyrus A1 - Cooper, Leslie T A1 - Coppola, Luis M A1 - Cortinovis, Monica A1 - Criqui, Michael H A1 - Crump, John A A1 - Cuevas-Nasu, Lucia A1 - Danawi, Hadi A1 - Dandona, Lalit A1 - Dandona, Rakhi A1 - Dansereau, Emily A1 - Dargan, Paul I A1 - Davey, Gail A1 - Davis, Adrian A1 - Davitoiu, Dragos V A1 - Dayama, Anand A1 - De Leo, Diego A1 - Degenhardt, Louisa A1 - del Pozo-Cruz, Borja A1 - Dellavalle, Robert P A1 - Deribe, Kebede A1 - Derrett, Sarah A1 - Des Jarlais, Don C A1 - Dessalegn, Muluken A1 - Dharmaratne, Samath D A1 - Dherani, Mukesh K A1 - Diaz-Torné, Cesar A1 - Dicker, Daniel A1 - Ding, Eric L A1 - Dokova, Klara A1 - Dorsey, E Ray A1 - Driscoll, Tim R A1 - Duan, Leilei A1 - Duber, Herbert C A1 - Ebel, Beth E A1 - Edmond, Karen M A1 - Elshrek, Yousef M A1 - Endres, Matthias A1 - Ermakov, Sergey P A1 - Erskine, Holly E A1 - Eshrati, Babak A1 - Esteghamati, Alireza A1 - Estep, Kara A1 - Faraon, Emerito Jose A A1 - Farzadfar, Farshad A1 - Fay, Derek F A1 - Feigin, Valery L A1 - Felson, David T A1 - Fereshtehnejad, Seyed-Mohammad A1 - Fernandes, Jefferson G A1 - Ferrari, Alize J A1 - Fitzmaurice, Christina A1 - Flaxman, Abraham D A1 - Fleming, Thomas D A1 - Foigt, Nataliya A1 - Forouzanfar, Mohammad H A1 - Fowkes, F Gerry R A1 - Paleo, Urbano Fra A1 - Franklin, Richard C A1 - Fürst, Thomas A1 - Gabbe, Belinda A1 - Gaffikin, Lynne A1 - Gankpé, Fortuné G A1 - Geleijnse, Johanna M A1 - Gessner, Bradford D A1 - Gething, Peter A1 - Gibney, Katherine B A1 - Giroud, Maurice A1 - Giussani, Giorgia A1 - Gomez Dantes, Hector A1 - Gona, Philimon A1 - Gonzalez-Medina, Diego A1 - Gosselin, Richard A A1 - Gotay, Carolyn C A1 - Goto, Atsushi A1 - Gouda, Hebe N A1 - Graetz, Nicholas A1 - Gugnani, Harish C A1 - Gupta, Rahul A1 - Gupta, Rajeev A1 - Gutiérrez, Reyna A A1 - Haagsma, Juanita A1 - Hafezi-Nejad, Nima A1 - Hagan, Holly A1 - Halasa, Yara A A1 - Hamadeh, Randah R A1 - Hamavid, Hannah A1 - Hammami, Mouhanad A1 - Hancock, Jamie A1 - Hankey, Graeme J A1 - Hansen, Gillian M A1 - Hao, Yuantao A1 - Harb, Hilda L A1 - Haro, Josep Maria A1 - Havmoeller, Rasmus A1 - Hay, Simon I A1 - Hay, Roderick J A1 - Heredia-Pi, Ileana B A1 - Heuton, Kyle R A1 - Heydarpour, Pouria A1 - Higashi, Hideki A1 - Hijar, Martha A1 - Hoek, Hans W A1 - Hoffman, Howard J A1 - Hosgood, H Dean A1 - Hossain, Mazeda A1 - Hotez, Peter J A1 - Hoy, Damian G A1 - Hsairi, Mohamed A1 - Hu, Guoqing A1 - Huang, Cheng A1 - Huang, John J A1 - Husseini, Abdullatif A1 - Huynh, Chantal A1 - Iannarone, Marissa L A1 - Iburg, Kim M A1 - Innos, Kaire A1 - Inoue, Manami A1 - Islami, Farhad A1 - Jacobsen, Kathryn H A1 - Jarvis, Deborah L A1 - Jassal, Simerjot K A1 - Jee, Sun Ha A1 - Jeemon, Panniyammakal A1 - Jensen, Paul N A1 - Jha, Vivekanand A1 - Jiang, Guohong A1 - Jiang, Ying A1 - Jonas, Jost B A1 - Juel, Knud A1 - Kan, Haidong A1 - Karch, André A1 - Karema, Corine K A1 - Karimkhani, Chante A1 - Karthikeyan, Ganesan A1 - Kassebaum, Nicholas J A1 - Kaul, Anil A1 - Kawakami, Norito A1 - Kazanjan, Konstantin A1 - Kemp, Andrew H A1 - Kengne, Andre P A1 - Keren, Andre A1 - Khader, Yousef S A1 - Khalifa, Shams Eldin A A1 - Khan, Ejaz A A1 - Khan, Gulfaraz A1 - Khang, Young-Ho A1 - Kieling, Christian A1 - Kim, Daniel A1 - Kim, Sungroul A1 - Kim, Yunjin A1 - Kinfu, Yohannes A1 - Kinge, Jonas M A1 - Kivipelto, Miia A1 - Knibbs, Luke D A1 - Knudsen, Ann Kristin A1 - Kokubo, Yoshihiro A1 - Kosen, Soewarta A1 - Krishnaswami, Sanjay A1 - Kuate Defo, Barthelemy A1 - Kucuk Bicer, Burcu A1 - Kuipers, Ernst J A1 - Kulkarni, Chanda A1 - Kulkarni, Veena S A1 - Kumar, G Anil A1 - Kyu, Hmwe H A1 - Lai, Taavi A1 - Lalloo, Ratilal A1 - Lallukka, Tea A1 - Lam, Hilton A1 - Lan, Qing A1 - Lansingh, Van C A1 - Larsson, Anders A1 - Lawrynowicz, Alicia E B A1 - Leasher, Janet L A1 - Leigh, James A1 - Leung, Ricky A1 - Levitz, Carly E A1 - Li, Bin A1 - Li, Yichong A1 - Li, Yongmei A1 - Lim, Stephen S A1 - Lind, Maggie A1 - Lipshultz, Steven E A1 - Liu, Shiwei A1 - Liu, Yang A1 - Lloyd, Belinda K A1 - Lofgren, Katherine T A1 - Logroscino, Giancarlo A1 - Looker, Katharine J A1 - Lortet-Tieulent, Joannie A1 - Lotufo, Paulo A A1 - Lozano, Rafael A1 - Lucas, Robyn M A1 - Lunevicius, Raimundas A1 - Lyons, Ronan A A1 - Ma, Stefan A1 - MacIntyre, Michael F A1 - Mackay, Mark T A1 - Majdan, Marek A1 - Malekzadeh, Reza A1 - Marcenes, Wagner A1 - Margolis, David J A1 - Margono, Christopher A1 - Marzan, Melvin B A1 - Masci, Joseph R A1 - Mashal, Mohammad T A1 - Matzopoulos, Richard A1 - Mayosi, Bongani M A1 - Mazorodze, Tasara T A1 - Mcgill, Neil W A1 - McGrath, John J A1 - McKee, Martin A1 - McLain, Abigail A1 - Meaney, Peter A A1 - Medina, Catalina A1 - Mehndiratta, Man Mohan A1 - Mekonnen, Wubegzier A1 - Melaku, Yohannes A A1 - Meltzer, Michele A1 - Memish, Ziad A A1 - Mensah, George A A1 - Meretoja, Atte A1 - Mhimbira, Francis A A1 - Micha, Renata A1 - Miller, Ted R A1 - Mills, Edward J A1 - Mitchell, Philip B A1 - Mock, Charles N A1 - Mohamed Ibrahim, Norlinah A1 - Mohammad, Karzan A A1 - Mokdad, Ali H A1 - Mola, Glen L D A1 - Monasta, Lorenzo A1 - Montañez Hernandez, Julio C A1 - Montico, Marcella A1 - Montine, Thomas J A1 - Mooney, Meghan D A1 - Moore, Ami R A1 - Moradi-Lakeh, Maziar A1 - Moran, Andrew E A1 - Mori, Rintaro A1 - Moschandreas, Joanna A1 - Moturi, Wilkister N A1 - Moyer, Madeline L A1 - Mozaffarian, Dariush A1 - Msemburi, William T A1 - Mueller, Ulrich O A1 - Mukaigawara, Mitsuru A1 - Mullany, Erin C A1 - Murdoch, Michele E A1 - Murray, Joseph A1 - Murthy, Kinnari S A1 - Naghavi, Mohsen A1 - Naheed, Aliya A1 - Naidoo, Kovin S A1 - Naldi, Luigi A1 - Nand, Devina A1 - Nangia, Vinay A1 - Narayan, K M Venkat A1 - Nejjari, Chakib A1 - Neupane, Sudan P A1 - Newton, Charles R A1 - Ng, Marie A1 - Ngalesoni, Frida N A1 - Nguyen, Grant A1 - Nisar, Muhammad I A1 - Nolte, Sandra A1 - Norheim, Ole F A1 - Norman, Rosana E A1 - Norrving, Bo A1 - Nyakarahuka, Luke A1 - Oh, In-Hwan A1 - Ohkubo, Takayoshi A1 - Ohno, Summer L A1 - Olusanya, Bolajoko O A1 - Opio, John Nelson A1 - Ortblad, Katrina A1 - Ortiz, Alberto A1 - Pain, Amanda W A1 - Pandian, Jeyaraj D A1 - Panelo, Carlo Irwin A A1 - Papachristou, Christina A1 - Park, Eun-Kee A1 - Park, Jae-Hyun A1 - Patten, Scott B A1 - Patton, George C A1 - Paul, Vinod K A1 - Pavlin, Boris I A1 - Pearce, Neil A1 - Pereira, David M A1 - Perez-Padilla, Rogelio A1 - Perez-Ruiz, Fernando A1 - Perico, Norberto A1 - Pervaiz, Aslam A1 - Pesudovs, Konrad A1 - Peterson, Carrie B A1 - Petzold, Max A1 - Phillips, Michael R A1 - Phillips, Bryan K A1 - Phillips, David E A1 - Piel, Frédéric B A1 - Plass, Dietrich A1 - Poenaru, Dan A1 - Polinder, Suzanne A1 - Pope, Daniel A1 - Popova, Svetlana A1 - Poulton, Richie G A1 - Pourmalek, Farshad A1 - Prabhakaran, Dorairaj A1 - Prasad, Noela M A1 - Pullan, Rachel L A1 - Qato, Dima M A1 - Quistberg, D Alex A1 - Rafay, Anwar A1 - Rahimi, Kazem A1 - Rahman, Sajjad U A1 - Raju, Murugesan A1 - Rana, Saleem M A1 - Razavi, Homie A1 - Reddy, K Srinath A1 - Refaat, Amany A1 - Remuzzi, Giuseppe A1 - Resnikoff, Serge A1 - Ribeiro, Antonio L A1 - Richardson, Lee A1 - Richardus, Jan Hendrik A1 - Roberts, D Allen A1 - Rojas-Rueda, David A1 - Ronfani, Luca A1 - Roth, Gregory A A1 - Rothenbacher, Dietrich A1 - Rothstein, David H A1 - Rowley, Jane T A1 - Roy, Nobhojit A1 - Ruhago, George M A1 - Saeedi, Mohammad Y A1 - Saha, Sukanta A1 - Sahraian, Mohammad Ali A1 - Sampson, Uchechukwu K A A1 - Sanabria, Juan R A1 - Sandar, Logan A1 - Santos, Itamar S A1 - Satpathy, Maheswar A1 - Sawhney, Monika A1 - Scarborough, Peter A1 - Schneider, Ione J A1 - Schöttker, Ben A1 - Schumacher, Austin E A1 - Schwebel, David C A1 - Scott, James G A1 - Seedat, Soraya A1 - Sepanlou, Sadaf G A1 - Serina, Peter T A1 - Servan-Mori, Edson E A1 - Shackelford, Katya A A1 - Shaheen, Amira A1 - Shahraz, Saeid A1 - Shamah Levy, Teresa A1 - Shangguan, Siyi A1 - She, Jun A1 - Sheikhbahaei, Sara A1 - Shi, Peilin A1 - Shibuya, Kenji A1 - Shinohara, Yukito A1 - Shiri, Rahman A1 - Shishani, Kawkab A1 - Shiue, Ivy A1 - Shrime, Mark G A1 - Sigfusdottir, Inga D A1 - Silberberg, Donald H A1 - Simard, Edgar P A1 - Sindi, Shireen A1 - Singh, Abhishek A1 - Singh, Jasvinder A A1 - Singh, Lavanya A1 - Skirbekk, Vegard A1 - Slepak, Erica Leigh A1 - Sliwa, Karen A1 - Soneji, Samir A1 - Søreide, Kjetil A1 - Soshnikov, Sergey A1 - Sposato, Luciano A A1 - Sreeramareddy, Chandrashekhar T A1 - Stanaway, Jeffrey D A1 - Stathopoulou, Vasiliki A1 - Stein, Dan J A1 - Stein, Murray B A1 - Steiner, Caitlyn A1 - Steiner, Timothy J A1 - Stevens, Antony A1 - Stewart, Andrea A1 - Stovner, Lars J A1 - Stroumpoulis, Konstantinos A1 - Sunguya, Bruno F A1 - Swaminathan, Soumya A1 - Swaroop, Mamta A1 - Sykes, Bryan L A1 - Tabb, Karen M A1 - Takahashi, Ken A1 - Tandon, Nikhil A1 - Tanne, David A1 - Tanner, Marcel A1 - Tavakkoli, Mohammad A1 - Taylor, Hugh R A1 - Te Ao, Braden J A1 - Tediosi, Fabrizio A1 - Temesgen, Awoke M A1 - Templin, Tara A1 - Ten Have, Margreet A1 - Tenkorang, Eric Y A1 - Terkawi, Abdullah S A1 - Thomson, Blake A1 - Thorne-Lyman, Andrew L A1 - Thrift, Amanda G A1 - Thurston, George D A1 - Tillmann, Taavi A1 - Tonelli, Marcello A1 - Topouzis, Fotis A1 - Toyoshima, Hideaki A1 - Traebert, Jefferson A1 - Tran, Bach X A1 - Trillini, Matias A1 - Truelsen, Thomas A1 - Tsilimbaris, Miltiadis A1 - Tuzcu, Emin M A1 - Uchendu, Uche S A1 - Ukwaja, Kingsley N A1 - Undurraga, Eduardo A A1 - Uzun, Selen B A1 - Van Brakel, Wim H A1 - van de Vijver, Steven A1 - van Gool, Coen H A1 - van Os, Jim A1 - Vasankari, Tommi J A1 - Venketasubramanian, N A1 - Violante, Francesco S A1 - Vlassov, Vasiliy V A1 - Vollset, Stein Emil A1 - Wagner, Gregory R A1 - Wagner, Joseph A1 - Waller, Stephen G A1 - Wan, Xia A1 - Wang, Haidong A1 - Wang, JianLi A1 - Wang, Linhong A1 - Warouw, Tati S A1 - Weichenthal, Scott A1 - Weiderpass, Elisabete A1 - Weintraub, Robert G A1 - Wenzhi, Wang A1 - Werdecker, Andrea A1 - Westerman, Ronny A1 - Whiteford, Harvey A A1 - Wilkinson, James D A1 - Williams, Thomas N A1 - Wolfe, Charles D A1 - Wolock, Timothy M A1 - Woolf, Anthony D A1 - Wulf, Sarah A1 - Wurtz, Brittany A1 - Xu, Gelin A1 - Yan, Lijing L A1 - Yano, Yuichiro A1 - Ye, Pengpeng A1 - Yentür, Gökalp K A1 - Yip, Paul A1 - Yonemoto, Naohiro A1 - Yoon, Seok-Jun A1 - Younis, Mustafa Z A1 - Yu, Chuanhua A1 - Zaki, Maysaa E A1 - Zhao, Yong A1 - Zheng, Yingfeng A1 - Zonies, David A1 - Zou, Xiaonong A1 - Salomon, Joshua A A1 - Lopez, Alan D A1 - Vos, Theo KW - Aged KW - Chronic Disease KW - Communicable Diseases KW - Female KW - Global Health KW - Health Transition KW - Humans KW - Life Expectancy KW - Male KW - Middle Aged KW - Mortality, Premature KW - Quality-Adjusted Life Years KW - Socioeconomic Factors KW - Wounds and Injuries AB -

BACKGROUND: The Global Burden of Disease Study 2013 (GBD 2013) aims to bring together all available epidemiological data using a coherent measurement framework, standardised estimation methods, and transparent data sources to enable comparisons of health loss over time and across causes, age-sex groups, and countries. The GBD can be used to generate summary measures such as disability-adjusted life-years (DALYs) and healthy life expectancy (HALE) that make possible comparative assessments of broad epidemiological patterns across countries and time. These summary measures can also be used to quantify the component of variation in epidemiology that is related to sociodemographic development.

METHODS: We used the published GBD 2013 data for age-specific mortality, years of life lost due to premature mortality (YLLs), and years lived with disability (YLDs) to calculate DALYs and HALE for 1990, 1995, 2000, 2005, 2010, and 2013 for 188 countries. We calculated HALE using the Sullivan method; 95% uncertainty intervals (UIs) represent uncertainty in age-specific death rates and YLDs per person for each country, age, sex, and year. We estimated DALYs for 306 causes for each country as the sum of YLLs and YLDs; 95% UIs represent uncertainty in YLL and YLD rates. We quantified patterns of the epidemiological transition with a composite indicator of sociodemographic status, which we constructed from income per person, average years of schooling after age 15 years, and the total fertility rate and mean age of the population. We applied hierarchical regression to DALY rates by cause across countries to decompose variance related to the sociodemographic status variable, country, and time.

FINDINGS: Worldwide, from 1990 to 2013, life expectancy at birth rose by 6·2 years (95% UI 5·6-6·6), from 65·3 years (65·0-65·6) in 1990 to 71·5 years (71·0-71·9) in 2013, HALE at birth rose by 5·4 years (4·9-5·8), from 56·9 years (54·5-59·1) to 62·3 years (59·7-64·8), total DALYs fell by 3·6% (0·3-7·4), and age-standardised DALY rates per 100 000 people fell by 26·7% (24·6-29·1). For communicable, maternal, neonatal, and nutritional disorders, global DALY numbers, crude rates, and age-standardised rates have all declined between 1990 and 2013, whereas for non-communicable diseases, global DALYs have been increasing, DALY rates have remained nearly constant, and age-standardised DALY rates declined during the same period. From 2005 to 2013, the number of DALYs increased for most specific non-communicable diseases, including cardiovascular diseases and neoplasms, in addition to dengue, food-borne trematodes, and leishmaniasis; DALYs decreased for nearly all other causes. By 2013, the five leading causes of DALYs were ischaemic heart disease, lower respiratory infections, cerebrovascular disease, low back and neck pain, and road injuries. Sociodemographic status explained more than 50% of the variance between countries and over time for diarrhoea, lower respiratory infections, and other common infectious diseases; maternal disorders; neonatal disorders; nutritional deficiencies; other communicable, maternal, neonatal, and nutritional diseases; musculoskeletal disorders; and other non-communicable diseases. However, sociodemographic status explained less than 10% of the variance in DALY rates for cardiovascular diseases; chronic respiratory diseases; cirrhosis; diabetes, urogenital, blood, and endocrine diseases; unintentional injuries; and self-harm and interpersonal violence. Predictably, increased sociodemographic status was associated with a shift in burden from YLLs to YLDs, driven by declines in YLLs and increases in YLDs from musculoskeletal disorders, neurological disorders, and mental and substance use disorders. In most country-specific estimates, the increase in life expectancy was greater than that in HALE. Leading causes of DALYs are highly variable across countries.

INTERPRETATION: Global health is improving. Population growth and ageing have driven up numbers of DALYs, but crude rates have remained relatively constant, showing that progress in health does not mean fewer demands on health systems. The notion of an epidemiological transition--in which increasing sociodemographic status brings structured change in disease burden--is useful, but there is tremendous variation in burden of disease that is not associated with sociodemographic status. This further underscores the need for country-specific assessments of DALYs and HALE to appropriately inform health policy decisions and attendant actions.

FUNDING: Bill & Melinda Gates Foundation.

VL - 386 IS - 10009 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26321261?dopt=Abstract ER - TY - JOUR T1 - Impaired immune response to Candida albicans in cells from Fanconi anemia patients. JF - Cytokine Y1 - 2015 A1 - Parodi, Alessia A1 - Kalli, Francesca A1 - Svahn, Johanna A1 - Stroppiana, Giorgia A1 - De Rocco, Daniela A1 - Terranova, Paola A1 - Dufour, Carlo A1 - Fenoglio, Daniela A1 - Cappelli, Enrico KW - Adolescent KW - Candida albicans KW - CD8-Positive T-Lymphocytes KW - Cell Proliferation KW - Cells, Cultured KW - Child KW - Child, Preschool KW - Cytokines KW - Fanconi Anemia KW - Humans KW - Immunity KW - Infant KW - Young Adult AB -

Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure and cancer predisposition. Several studies show alterations of the immunological status of FA patients including defects in peripheral blood lymphocyte subsets, serum immunoglobulin levels, and inflammatory cytokines. However scanty information is available on the response of FA cells to specific infectious antigens. In this work we examined the response of FA cells to different immunological stimuli and found a defective response of IL-1β, TNF-α and IL-17 to Candida albicans stimulation thus pointing to a potentially impaired response to fungal infections of FA patients.

VL - 73 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25769809?dopt=Abstract ER - TY - JOUR T1 - The Kalash genetic isolate: ancient divergence, drift, and selection. JF - Am J Hum Genet Y1 - 2015 A1 - Ayub, Qasim A1 - Mezzavilla, Massimo A1 - Pagani, Luca A1 - Haber, Marc A1 - Mohyuddin, Aisha A1 - Khaliq, Shagufta A1 - Mehdi, Syed Qasim A1 - Tyler-Smith, Chris KW - Asia KW - Asian Continental Ancestry Group KW - Chromosomes, Human, Y KW - Demography KW - DNA, Mitochondrial KW - European Continental Ancestry Group KW - Genetic Drift KW - Genetics, Population KW - Haplotypes KW - History, Ancient KW - Humans KW - Male KW - Pakistan KW - Phylogeny AB -

The Kalash represent an enigmatic isolated population of Indo-European speakers who have been living for centuries in the Hindu Kush mountain ranges of present-day Pakistan. Previous Y chromosome and mitochondrial DNA markers provided no support for their claimed Greek descent following Alexander III of Macedon's invasion of this region, and analysis of autosomal loci provided evidence of a strong genetic bottleneck. To understand their origins and demography further, we genotyped 23 unrelated Kalash samples on the Illumina HumanOmni2.5M-8 BeadChip and sequenced one male individual at high coverage on an Illumina HiSeq 2000. Comparison with published data from ancient hunter-gatherers and European farmers showed that the Kalash share genetic drift with the Paleolithic Siberian hunter-gatherers and might represent an extremely drifted ancient northern Eurasian population that also contributed to European and Near Eastern ancestry. Since the split from other South Asian populations, the Kalash have maintained a low long-term effective population size (2,319-2,603) and experienced no detectable gene flow from their geographic neighbors in Pakistan or from other extant Eurasian populations. The mean time of divergence between the Kalash and other populations currently residing in this region was estimated to be 11,800 (95% confidence interval = 10,600-12,600) years ago, and thus they represent present-day descendants of some of the earliest migrants into the Indian sub-continent from West Asia.

VL - 96 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25937445?dopt=Abstract ER - TY - JOUR T1 - Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. JF - Nat Genet Y1 - 2015 A1 - Day, Felix R A1 - Ruth, Katherine S A1 - Thompson, Deborah J A1 - Lunetta, Kathryn L A1 - Pervjakova, Natalia A1 - Chasman, Daniel I A1 - Stolk, Lisette A1 - Finucane, Hilary K A1 - Sulem, Patrick A1 - Bulik-Sullivan, Brendan A1 - Esko, Tõnu A1 - Johnson, Andrew D A1 - Elks, Cathy E A1 - Franceschini, Nora A1 - He, Chunyan A1 - Altmaier, Elisabeth A1 - Brody, Jennifer A A1 - Franke, Lude L A1 - Huffman, Jennifer E A1 - Keller, Margaux F A1 - McArdle, Patrick F A1 - Nutile, Teresa A1 - Porcu, Eleonora A1 - Robino, Antonietta A1 - Rose, Lynda M A1 - Schick, Ursula M A1 - Smith, Jennifer A A1 - Teumer, Alexander A1 - Traglia, Michela A1 - Vuckovic, Dragana A1 - Yao, Jie A1 - Zhao, Wei A1 - Albrecht, Eva A1 - Amin, Najaf A1 - Corre, Tanguy A1 - Hottenga, Jouke-Jan A1 - Mangino, Massimo A1 - Smith, Albert V A1 - Tanaka, Toshiko A1 - Abecasis, Goncalo R A1 - Andrulis, Irene L A1 - Anton-Culver, Hoda A1 - Antoniou, Antonis C A1 - Arndt, Volker A1 - Arnold, Alice M A1 - Barbieri, Caterina A1 - Beckmann, Matthias W A1 - Beeghly-Fadiel, Alicia A1 - Benitez, Javier A1 - Bernstein, Leslie A1 - Bielinski, Suzette J A1 - Blomqvist, Carl A1 - Boerwinkle, Eric A1 - Bogdanova, Natalia V A1 - Bojesen, Stig E A1 - Bolla, Manjeet K A1 - Borresen-Dale, Anne-Lise A1 - Boutin, Thibaud S A1 - Brauch, Hiltrud A1 - Brenner, Hermann A1 - Brüning, Thomas A1 - Burwinkel, Barbara A1 - Campbell, Archie A1 - Campbell, Harry A1 - Chanock, Stephen J A1 - Chapman, J Ross A1 - Chen, Yii-Der Ida A1 - Chenevix-Trench, Georgia A1 - Couch, Fergus J A1 - Coviello, Andrea D A1 - Cox, Angela A1 - Czene, Kamila A1 - Darabi, Hatef A1 - De Vivo, Immaculata A1 - Demerath, Ellen W A1 - Dennis, Joe A1 - Devilee, Peter A1 - Dörk, Thilo A1 - Dos-Santos-Silva, Isabel A1 - Dunning, Alison M A1 - Eicher, John D A1 - Fasching, Peter A A1 - Faul, Jessica D A1 - Figueroa, Jonine A1 - Flesch-Janys, Dieter A1 - Gandin, Ilaria A1 - Garcia, Melissa E A1 - García-Closas, Montserrat A1 - Giles, Graham G A1 - Girotto, Giorgia G A1 - Goldberg, Mark S A1 - González-Neira, Anna A1 - Goodarzi, Mark O A1 - Grove, Megan L A1 - Gudbjartsson, Daniel F A1 - Guenel, Pascal A1 - Guo, Xiuqing A1 - Haiman, Christopher A A1 - Hall, Per A1 - Hamann, Ute A1 - Henderson, Brian E A1 - Hocking, Lynne J A1 - Hofman, Albert A1 - Homuth, Georg A1 - Hooning, Maartje J A1 - Hopper, John L A1 - Hu, Frank B A1 - Huang, Jinyan A1 - Humphreys, Keith A1 - Hunter, David J A1 - Jakubowska, Anna A1 - Jones, Samuel E A1 - Kabisch, Maria A1 - Karasik, David A1 - Knight, Julia A A1 - Kolcic, Ivana A1 - Kooperberg, Charles A1 - Kosma, Veli-Matti A1 - Kriebel, Jennifer A1 - Kristensen, Vessela A1 - Lambrechts, Diether A1 - Langenberg, Claudia A1 - Li, Jingmei A1 - Li, Xin A1 - Lindström, Sara A1 - Liu, Yongmei A1 - Luan, Jian'an A1 - Lubinski, Jan A1 - Mägi, Reedik A1 - Mannermaa, Arto A1 - Manz, Judith A1 - Margolin, Sara A1 - Marten, Jonathan A1 - Martin, Nicholas G A1 - Masciullo, Corrado A1 - Meindl, Alfons A1 - Michailidou, Kyriaki A1 - Mihailov, Evelin A1 - Milani, Lili A1 - Milne, Roger L A1 - Müller-Nurasyid, Martina A1 - Nalls, Michael A1 - Neale, Benjamin M A1 - Nevanlinna, Heli A1 - Neven, Patrick A1 - Newman, Anne B A1 - Nordestgaard, Børge G A1 - Olson, Janet E A1 - Padmanabhan, Sandosh A1 - Peterlongo, Paolo A1 - Peters, Ulrike A1 - Petersmann, Astrid A1 - Peto, Julian A1 - Pharoah, Paul D P A1 - Pirastu, Nicola N A1 - Pirie, Ailith A1 - Pistis, Giorgio A1 - Polasek, Ozren A1 - Porteous, David A1 - Psaty, Bruce M A1 - Pylkäs, Katri A1 - Radice, Paolo A1 - Raffel, Leslie J A1 - Rivadeneira, Fernando A1 - Rudan, Igor A1 - Rudolph, Anja A1 - Ruggiero, Daniela A1 - Sala, Cinzia F A1 - Sanna, Serena A1 - Sawyer, Elinor J A1 - Schlessinger, David A1 - Schmidt, Marjanka K A1 - Schmidt, Frank A1 - Schmutzler, Rita K A1 - Schoemaker, Minouk J A1 - Scott, Robert A A1 - Seynaeve, Caroline M A1 - Simard, Jacques A1 - Sorice, Rossella A1 - Southey, Melissa C A1 - Stöckl, Doris A1 - Strauch, Konstantin A1 - Swerdlow, Anthony A1 - Taylor, Kent D A1 - Thorsteinsdottir, Unnur A1 - Toland, Amanda E A1 - Tomlinson, Ian A1 - Truong, Therese A1 - Tryggvadottir, Laufey A1 - Turner, Stephen T A1 - Vozzi, Diego A1 - Wang, Qin A1 - Wellons, Melissa A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Winqvist, Robert A1 - Wolffenbuttel, Bruce B H R A1 - Wright, Alan F A1 - Yannoukakos, Drakoulis A1 - Zemunik, Tatijana A1 - Zheng, Wei A1 - Zygmunt, Marek A1 - Bergmann, Sven A1 - Boomsma, Dorret I A1 - Buring, Julie E A1 - Ferrucci, Luigi A1 - Montgomery, Grant W A1 - Gudnason, Vilmundur A1 - Spector, Tim D A1 - van Duijn, Cornelia M A1 - Alizadeh, Behrooz Z A1 - Ciullo, Marina A1 - Crisponi, Laura A1 - Easton, Douglas F A1 - Gasparini, Paolo P A1 - Gieger, Christian A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Kardia, Sharon L R A1 - Kraft, Peter A1 - McKnight, Barbara A1 - Metspalu, Andres A1 - Morrison, Alanna C A1 - Reiner, Alex P A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - Toniolo, Daniela A1 - Uitterlinden, André G A1 - Ulivi, Sheila A1 - Völzke, Henry A1 - Wareham, Nicholas J A1 - Weir, David R A1 - Yerges-Armstrong, Laura M A1 - Price, Alkes L A1 - Stefansson, Kari A1 - Visser, Jenny A A1 - Ong, Ken K A1 - Chang-Claude, Jenny A1 - Murabito, Joanne M A1 - Perry, John R B A1 - Murray, Anna AB -

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

VL - 47 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26414677?dopt=Abstract ER - TY - JOUR T1 - Making the first days of life safer: preventing sudden unexpected postnatal collapse while promoting breastfeeding. JF - J Hum Lact Y1 - 2015 A1 - Davanzo, Riccardo A1 - De Cunto, Angela A1 - Paviotti, Giulia A1 - Travan, Laura A1 - Inglese, Stefania A1 - Brovedani, Pierpaolo A1 - Crocetta, Anna A1 - Calligaris, Chiara A1 - Corubolo, Elisa A1 - Dussich, Valentina A1 - Verardi, Giuseppa A1 - Causin, Enrica A1 - Kennedy, Jaquelyn A1 - Marrazzo, Francesca A1 - Strajn, Tamara A1 - Sanesi, Cecilia A1 - Demarini, Sergio AB -

Early and prolonged skin-to-skin contact (SSC) after birth between a mother and her newborn has been shown to generate beneficial effects on the mother-infant relationship and breastfeeding. Close mother-infant body contact immediately after birth positively enhances exclusive breastfeeding during the hospital stay, with a dose-response relationship. Skin-to-skin contact may ease the infant's transition to extra-uterine life and helps regulate the infant's body temperature and nursing behavior. However, reports of sudden unexpected postnatal collapse (SUPC) soon after birth, in healthy term neonates, in association with SSC, have raised concerns about the safety of this practice. Based on available evidence, we developed a surveillance protocol in the delivery room and postnatal ward of the Institute for Maternal and Child Health of Trieste (Italy). The aim of our protocol is (a) to promote safe mother and infant bonding and (b) to establish successful breastfeeding, without increasing the risk of SUPC. As there is no known effective intervention to prevent SUPC, our protocol has been conceived as a potential best practice.

VL - 31 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25339551?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis and time series modeling allow a systematic review of primary HIV-1 drug-resistant prevalence in Latin America and Caribbean. JF - Curr HIV Res Y1 - 2015 A1 - Coelho, Antônio Victor Campos A1 - De Moura, Ronald Rodrigues A1 - da Silva, Ronaldo Celerino A1 - Kamada, Anselmo Jiro A1 - Guimarães, Rafael Lima A1 - Brandão, Lucas André Cavalcanti A1 - Coelho, Hemílio Fernandes Campos A1 - Crovella, Sergio AB -

Here we review the prevalence of HIV-1 primary drug resistance in Latin America and Caribbean using meta-analysis as well as time-series modeling. We also discuss whether there could be a drawback to HIV/AIDS programs due to drug resistance in Latin America and Caribbean in the next years. We observed that, although some studies report low or moderate primary drug resistance prevalence in Caribbean countries, this evidence needs to be updated. In other countries, such as Brazil and Argentina, the prevalence of drug resistance appears to be rising. Mutations conferring resistance against reverse transcriptase inhibitors were the most frequent in the analyzed populations (70% of all mutational events). HIV-1 subtype B was the most prevalent in Latin America and the Caribbean, although subtype C and B/F recombinants have significant contributions in Argentina and Brazil. Thus, we suggest that primary drug resistance in Latin America and the Caribbean could have been underestimated. Clinical monitoring should be improved to offer better therapy, reducing the risk for HIV-1 resistance emergence and spread, principally in vulnerable populations, such as men who have sex with men transmission group, sex workers and intravenous drug users.

VL - 13 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25777517?dopt=Abstract ER - TY - JOUR T1 - Microglia activation and interaction with neuronal cells in a biochemical model of mevalonate kinase deficiency. JF - Apoptosis Y1 - 2015 A1 - Tricarico, Paola Maura A1 - Piscianz, Elisa A1 - Monasta, Lorenzo A1 - Kleiner, Giulio A1 - Crovella, Sergio A1 - Marcuzzi, Annalisa AB -

Mevalonate kinase deficiency is a rare disease whose worst manifestation, characterised by severe neurologic impairment, is called mevalonic aciduria. The progressive neuronal loss associated to cell death can be studied in vitro with a simplified model based on a biochemical block of the mevalonate pathway and a subsequent inflammatory trigger. The aim of this study was to evaluate the effect of the mevalonate blocking on glial cells (BV-2) and the following effects on neuronal cells (SH-SY5Y) when the two populations were cultured together. To better understand the cross-talk between glial and neuronal cells, as it happens in vivo, BV-2 and SH-SY5Y were co-cultured in different experimental settings (alone, transwell, direct contact); the effect of mevalonate pathway biochemical block by Lovastatin, followed by LPS inflammatory trigger, were evaluated by analysing programmed cell death and mitochondrial membrane potential, cytokines' release and cells' morphology modifications. In this experimental condition, glial cells underwent an evident activation, confirmed by elevated pro-inflammatory cytokines release, typical of these disorders, and a modification in morphology. Moreover, the activation induced an increase in apoptosis. When glial cells were co-cultured with neurons, their activation caused an increase of programmed cell death also in neuronal cells, but only if the two populations were cultured in direct contact. Our findings, being aware of the limitations related to the cell models used, represent a preliminary step towards understanding the pathological and neuroinflammatory mechanisms occurring in mevalonate kinase diseases. Contact co-culture between neuronal and microglial cells seems to be a good model to study mevalonic aciduria in vitro, and to contribute to the identification of potential drugs able to block microglial activation for this orphan disease. In fact, in such a pathological condition, we demonstrated that microglial cells are activated and contribute to neuronal cell death. We can thus hypothesise that the use of microglial activation blockers could prevent this additional neuronal death.

VL - 20 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26003816?dopt=Abstract ER - TY - JOUR T1 - Modulation of genetic associations with serum urate levels by body-mass-index in humans. JF - PLoS One Y1 - 2015 A1 - Huffman, Jennifer E A1 - Albrecht, Eva A1 - Teumer, Alexander A1 - Mangino, Massimo A1 - Kapur, Karen A1 - Johnson, Toby A1 - Kutalik, Zoltán A1 - Pirastu, Nicola A1 - Pistis, Giorgio A1 - Lopez, Lorna M A1 - Haller, Toomas A1 - Salo, Perttu A1 - Goel, Anuj A1 - Li, Man A1 - Tanaka, Toshiko A1 - Dehghan, Abbas A1 - Ruggiero, Daniela A1 - Malerba, Giovanni A1 - Smith, Albert V A1 - Nolte, Ilja M A1 - Portas, Laura A1 - Phipps-Green, Amanda A1 - Boteva, Lora A1 - Navarro, Pau A1 - Johansson, Åsa A1 - Hicks, Andrew A A1 - Polasek, Ozren A1 - Esko, Tõnu A1 - Peden, John F A1 - Harris, Sarah E A1 - Murgia, Federico A1 - Wild, Sarah H A1 - Tenesa, Albert A1 - Tin, Adrienne A1 - Mihailov, Evelin A1 - Grotevendt, Anne A1 - Gislason, Gauti K A1 - Coresh, Josef A1 - d'Adamo, Pio A1 - Ulivi, Sheila A1 - Vollenweider, Peter A1 - Waeber, Gerard A1 - Campbell, Susan A1 - Kolcic, Ivana A1 - Fisher, Krista A1 - Viigimaa, Margus A1 - Metter, Jeffrey E A1 - Masciullo, Corrado A1 - Trabetti, Elisabetta A1 - Bombieri, Cristina A1 - Sorice, Rossella A1 - Döring, Angela A1 - Reischl, Eva A1 - Strauch, Konstantin A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Waldenberger, Melanie A1 - Wichmann, H-Erich A1 - Davies, Gail A1 - Gow, Alan J A1 - Dalbeth, Nicola A1 - Stamp, Lisa A1 - Smit, Johannes H A1 - Kirin, Mirna A1 - Nagaraja, Ramaiah A1 - Nauck, Matthias A1 - Schurmann, Claudia A1 - Budde, Kathrin A1 - Farrington, Susan M A1 - Theodoratou, Evropi A1 - Jula, Antti A1 - Salomaa, Veikko A1 - Sala, Cinzia A1 - Hengstenberg, Christian A1 - Burnier, Michel A1 - Mägi, Reedik A1 - Klopp, Norman A1 - Kloiber, Stefan A1 - Schipf, Sabine A1 - Ripatti, Samuli A1 - Cabras, Stefano A1 - Soranzo, Nicole A1 - Homuth, Georg A1 - Nutile, Teresa A1 - Munroe, Patricia B A1 - Hastie, Nicholas A1 - Campbell, Harry A1 - Rudan, Igor A1 - Cabrera, Claudia A1 - Haley, Chris A1 - Franco, Oscar H A1 - Merriman, Tony R A1 - Gudnason, Vilmundur A1 - Pirastu, Mario A1 - Penninx, Brenda W A1 - Snieder, Harold A1 - Metspalu, Andres A1 - Ciullo, Marina A1 - Pramstaller, Peter P A1 - van Duijn, Cornelia M A1 - Ferrucci, Luigi A1 - Gambaro, Giovanni A1 - Deary, Ian J A1 - Dunlop, Malcolm G A1 - Wilson, James F A1 - Gasparini, Paolo A1 - Gyllensten, Ulf A1 - Spector, Tim D A1 - Wright, Alan F A1 - Hayward, Caroline A1 - Watkins, Hugh A1 - Perola, Markus A1 - Bochud, Murielle A1 - Kao, W H Linda A1 - Caulfield, Mark A1 - Toniolo, Daniela A1 - Völzke, Henry A1 - Gieger, Christian A1 - Köttgen, Anna A1 - Vitart, Veronique AB -

We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.

VL - 10 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25811787?dopt=Abstract ER - TY - JOUR T1 - New genetic loci link adipose and insulin biology to body fat distribution. JF - Nature Y1 - 2015 A1 - Shungin, Dmitry A1 - Winkler, Thomas W A1 - Croteau-Chonka, Damien C A1 - Ferreira, Teresa A1 - Locke, Adam E A1 - Mägi, Reedik A1 - Strawbridge, Rona J A1 - Pers, Tune H A1 - Fischer, Krista A1 - Justice, Anne E A1 - Workalemahu, Tsegaselassie A1 - Wu, Joseph M W A1 - Buchkovich, Martin L A1 - Heard-Costa, Nancy L A1 - Roman, Tamara S A1 - Drong, Alexander W A1 - Song, Ci A1 - Gustafsson, Stefan A1 - Day, Felix R A1 - Esko, Tõnu A1 - Fall, Tove A1 - Kutalik, Zoltán A1 - Luan, Jian'an A1 - Randall, Joshua C A1 - Scherag, André A1 - Vedantam, Sailaja A1 - Wood, Andrew R A1 - Chen, Jin A1 - Fehrmann, Rudolf A1 - Karjalainen, Juha A1 - Kahali, Bratati A1 - Liu, Ching-Ti A1 - Schmidt, Ellen M A1 - Absher, Devin A1 - Amin, Najaf A1 - Anderson, Denise A1 - Beekman, Marian A1 - Bragg-Gresham, Jennifer L A1 - Buyske, Steven A1 - Demirkan, Ayse A1 - Ehret, Georg B A1 - Feitosa, Mary F A1 - Goel, Anuj A1 - Jackson, Anne U A1 - Johnson, Toby A1 - Kleber, Marcus E A1 - Kristiansson, Kati A1 - Mangino, Massimo A1 - Mateo Leach, Irene A1 - Medina-Gomez, Carolina A1 - Palmer, Cameron D A1 - Pasko, Dorota A1 - Pechlivanis, Sonali A1 - Peters, Marjolein J A1 - Prokopenko, Inga A1 - Stančáková, Alena A1 - Ju Sung, Yun A1 - Tanaka, Toshiko A1 - Teumer, Alexander A1 - Van Vliet-Ostaptchouk, Jana V A1 - Yengo, Loic A1 - Zhang, Weihua A1 - Albrecht, Eva A1 - Arnlöv, Johan A1 - Arscott, Gillian M A1 - Bandinelli, Stefania A1 - Barrett, Amy A1 - Bellis, Claire A1 - Bennett, Amanda J A1 - Berne, Christian A1 - Blüher, Matthias A1 - Böhringer, Stefan A1 - Bonnet, Fabrice A1 - Böttcher, Yvonne A1 - Bruinenberg, Marcel A1 - Carba, Delia B A1 - Caspersen, Ida H A1 - Clarke, Robert A1 - Daw, E Warwick A1 - Deelen, Joris A1 - Deelman, Ewa A1 - Delgado, Graciela A1 - Doney, Alex S F A1 - Eklund, Niina A1 - Erdos, Michael R A1 - Estrada, Karol A1 - Eury, Elodie A1 - Friedrich, Nele A1 - Garcia, Melissa E A1 - Giedraitis, Vilmantas A1 - Gigante, Bruna A1 - Go, Alan S A1 - Golay, Alain A1 - Grallert, Harald A1 - Grammer, Tanja B A1 - Gräßler, Jürgen A1 - Grewal, Jagvir A1 - Groves, Christopher J A1 - Haller, Toomas A1 - Hallmans, Goran A1 - Hartman, Catharina A A1 - Hassinen, Maija A1 - Hayward, Caroline A1 - Heikkilä, Kauko A1 - Herzig, Karl-Heinz A1 - Helmer, Quinta A1 - Hillege, Hans L A1 - Holmen, Oddgeir A1 - Hunt, Steven C A1 - Isaacs, Aaron A1 - Ittermann, Till A1 - James, Alan L A1 - Johansson, Ingegerd A1 - Juliusdottir, Thorhildur A1 - Kalafati, Ioanna-Panagiota A1 - Kinnunen, Leena A1 - Koenig, Wolfgang A1 - Kooner, Ishminder K A1 - Kratzer, Wolfgang A1 - Lamina, Claudia A1 - Leander, Karin A1 - Lee, Nanette R A1 - Lichtner, Peter A1 - Lind, Lars A1 - Lindström, Jaana A1 - Lobbens, Stéphane A1 - Lorentzon, Mattias A1 - Mach, François A1 - Magnusson, Patrik K E A1 - Mahajan, Anubha A1 - McArdle, Wendy L A1 - Menni, Cristina A1 - Merger, Sigrun A1 - Mihailov, Evelin A1 - Milani, Lili A1 - Mills, Rebecca A1 - Moayyeri, Alireza A1 - Monda, Keri L A1 - Mooijaart, Simon P A1 - Mühleisen, Thomas W A1 - Mulas, Antonella A1 - Müller, Gabriele A1 - Müller-Nurasyid, Martina A1 - Nagaraja, Ramaiah A1 - Nalls, Michael A A1 - Narisu, Narisu A1 - Glorioso, Nicola A1 - Nolte, Ilja M A1 - Olden, Matthias A1 - Rayner, Nigel W A1 - Renstrom, Frida A1 - Ried, Janina S A1 - Robertson, Neil R A1 - Rose, Lynda M A1 - Sanna, Serena A1 - Scharnagl, Hubert A1 - Scholtens, Salome A1 - Sennblad, Bengt A1 - Seufferlein, Thomas A1 - Sitlani, Colleen M A1 - Vernon Smith, Albert A1 - Stirrups, Kathleen A1 - Stringham, Heather M A1 - Sundström, Johan A1 - Swertz, Morris A A1 - Swift, Amy J A1 - Syvänen, Ann-Christine A1 - Tayo, Bamidele O A1 - Thorand, Barbara A1 - Thorleifsson, Gudmar A1 - Tomaschitz, Andreas A1 - Troffa, Chiara A1 - van Oort, Floor V A A1 - Verweij, Niek A1 - Vonk, Judith M A1 - Waite, Lindsay L A1 - Wennauer, Roman A1 - Wilsgaard, Tom A1 - Wojczynski, Mary K A1 - Wong, Andrew A1 - Zhang, Qunyuan A1 - Hua Zhao, Jing A1 - Brennan, Eoin P A1 - Choi, Murim A1 - Eriksson, Per A1 - Folkersen, Lasse A1 - Franco-Cereceda, Anders A1 - Gharavi, Ali G A1 - Hedman, Åsa K A1 - Hivert, Marie-France A1 - Huang, Jinyan A1 - Kanoni, Stavroula A1 - Karpe, Fredrik A1 - Keildson, Sarah A1 - Kiryluk, Krzysztof A1 - Liang, Liming A1 - Lifton, Richard P A1 - Ma, Baoshan A1 - McKnight, Amy J A1 - McPherson, Ruth A1 - Metspalu, Andres A1 - Min, Josine L A1 - Moffatt, Miriam F A1 - Montgomery, Grant W A1 - Murabito, Joanne M A1 - Nicholson, George A1 - Nyholt, Dale R A1 - Olsson, Christian A1 - Perry, John R B A1 - Reinmaa, Eva A1 - Salem, Rany M A1 - Sandholm, Niina A1 - Schadt, Eric E A1 - Scott, Robert A A1 - Stolk, Lisette A1 - Vallejo, Edgar E A1 - Westra, Harm-Jan A1 - Zondervan, Krina T A1 - Amouyel, Philippe A1 - Arveiler, Dominique A1 - Bakker, Stephan J L A1 - Beilby, John A1 - Bergman, Richard N A1 - Blangero, John A1 - Brown, Morris J A1 - Burnier, Michel A1 - Campbell, Harry A1 - Chakravarti, Aravinda A1 - Chines, Peter S A1 - Claudi-Boehm, Simone A1 - Collins, Francis S A1 - Crawford, Dana C A1 - Danesh, John A1 - de Faire, Ulf A1 - de Geus, Eco J C A1 - Dörr, Marcus A1 - Erbel, Raimund A1 - Eriksson, Johan G A1 - Farrall, Martin A1 - Ferrannini, Ele A1 - Ferrières, Jean A1 - Forouhi, Nita G A1 - Forrester, Terrence A1 - Franco, Oscar H A1 - Gansevoort, Ron T A1 - Gieger, Christian A1 - Gudnason, Vilmundur A1 - Haiman, Christopher A A1 - Harris, Tamara B A1 - Hattersley, Andrew T A1 - Heliövaara, Markku A1 - Hicks, Andrew A A1 - Hingorani, Aroon D A1 - Hoffmann, Wolfgang A1 - Hofman, Albert A1 - Homuth, Georg A1 - Humphries, Steve E A1 - Hyppönen, Elina A1 - Illig, Thomas A1 - Järvelin, Marjo-Riitta A1 - Johansen, Berit A1 - Jousilahti, Pekka A1 - Jula, Antti M A1 - Kaprio, Jaakko A1 - Kee, Frank A1 - Keinanen-Kiukaanniemi, Sirkka M A1 - Kooner, Jaspal S A1 - Kooperberg, Charles A1 - Kovacs, Peter A1 - Kraja, Aldi T A1 - Kumari, Meena A1 - Kuulasmaa, Kari A1 - Kuusisto, Johanna A1 - Lakka, Timo A A1 - Langenberg, Claudia A1 - Le Marchand, Loic A1 - Lehtimäki, Terho A1 - Lyssenko, Valeriya A1 - Männistö, Satu A1 - Marette, André A1 - Matise, Tara C A1 - McKenzie, Colin A A1 - McKnight, Barbara A1 - Musk, Arthur W A1 - Möhlenkamp, Stefan A1 - Morris, Andrew D A1 - Nelis, Mari A1 - Ohlsson, Claes A1 - Oldehinkel, Albertine J A1 - Ong, Ken K A1 - Palmer, Lyle J A1 - Penninx, Brenda W A1 - Peters, Annette A1 - Pramstaller, Peter P A1 - Raitakari, Olli T A1 - Rankinen, Tuomo A1 - Rao, D C A1 - Rice, Treva K A1 - Ridker, Paul M A1 - Ritchie, Marylyn D A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Saramies, Jouko A1 - Sarzynski, Mark A A1 - Schwarz, Peter E H A1 - Shuldiner, Alan R A1 - Staessen, Jan A A1 - Steinthorsdottir, Valgerdur A1 - Stolk, Ronald P A1 - Strauch, Konstantin A1 - Tönjes, Anke A1 - Tremblay, Angelo A1 - Tremoli, Elena A1 - Vohl, Marie-Claude A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Wilson, James F A1 - Witteman, Jacqueline C A1 - Adair, Linda S A1 - Bochud, Murielle A1 - Boehm, Bernhard O A1 - Bornstein, Stefan R A1 - Bouchard, Claude A1 - Cauchi, Stéphane A1 - Caulfield, Mark J A1 - Chambers, John C A1 - Chasman, Daniel I A1 - Cooper, Richard S A1 - Dedoussis, George A1 - Ferrucci, Luigi A1 - Froguel, Philippe A1 - Grabe, Hans-Jörgen A1 - Hamsten, Anders A1 - Hui, Jennie A1 - Hveem, Kristian A1 - Jöckel, Karl-Heinz A1 - Kivimaki, Mika A1 - Kuh, Diana A1 - Laakso, Markku A1 - Liu, Yongmei A1 - März, Winfried A1 - Munroe, Patricia B A1 - Njølstad, Inger A1 - Oostra, Ben A A1 - Palmer, Colin N A A1 - Pedersen, Nancy L A1 - Perola, Markus A1 - Pérusse, Louis A1 - Peters, Ulrike A1 - Power, Chris A1 - Quertermous, Thomas A1 - Rauramaa, Rainer A1 - Rivadeneira, Fernando A1 - Saaristo, Timo E A1 - Saleheen, Danish A1 - Sinisalo, Juha A1 - Slagboom, P Eline A1 - Snieder, Harold A1 - Spector, Tim D A1 - Thorsteinsdottir, Unnur A1 - Stumvoll, Michael A1 - Tuomilehto, Jaakko A1 - Uitterlinden, André G A1 - Uusitupa, Matti A1 - van der Harst, Pim A1 - Veronesi, Giovanni A1 - Walker, Mark A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Wichmann, H-Erich A1 - Abecasis, Goncalo R A1 - Assimes, Themistocles L A1 - Berndt, Sonja I A1 - Boehnke, Michael A1 - Borecki, Ingrid B A1 - Deloukas, Panos A1 - Franke, Lude A1 - Frayling, Timothy M A1 - Groop, Leif C A1 - Hunter, David J A1 - Kaplan, Robert C A1 - O'Connell, Jeffrey R A1 - Qi, Lu A1 - Schlessinger, David A1 - Strachan, David P A1 - Stefansson, Kari A1 - van Duijn, Cornelia M A1 - Willer, Cristen J A1 - Visscher, Peter M A1 - Yang, Jian A1 - Hirschhorn, Joel N A1 - Zillikens, M Carola A1 - McCarthy, Mark I A1 - Speliotes, Elizabeth K A1 - North, Kari E A1 - Fox, Caroline S A1 - Barroso, Inês A1 - Franks, Paul W A1 - Ingelsson, Erik A1 - Heid, Iris M A1 - Loos, Ruth J F A1 - Cupples, L Adrienne A1 - Morris, Andrew P A1 - Lindgren, Cecilia M A1 - Mohlke, Karen L KW - Adipocytes KW - Adipogenesis KW - Adipose Tissue KW - Age Factors KW - Body Fat Distribution KW - Body Mass Index KW - Continental Population Groups KW - Epigenesis, Genetic KW - Europe KW - Female KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Insulin KW - Insulin Resistance KW - Male KW - Models, Biological KW - Neovascularization, Physiologic KW - Obesity KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Sex Characteristics KW - Transcription, Genetic KW - Waist-Hip Ratio AB -

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

VL - 518 IS - 7538 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25673412?dopt=Abstract ER - TY - JOUR T1 - Pediatric patients with inflammatory bowel disease exhibit increased serum levels of proinflammatory cytokines and chemokines, but decreased circulating levels of macrophage inhibitory protein-1β, interleukin-2 and interleukin-17. JF - Exp Ther Med Y1 - 2015 A1 - Kleiner, Giulio A1 - Zanin, Valentina A1 - Monasta, Lorenzo A1 - Crovella, Sergio A1 - Caruso, Lorenzo A1 - Milani, Daniela A1 - Marcuzzi, Annalisa AB -

Inflammatory bowel disease (IBD) is a chronic and progressive inflammatory condition of the gastrointestinal tract. Although the causative events that lead to the onset of IBD are yet to be fully elucidated, deregulation of immune and inflammatory mechanisms are hypothesized to significantly contribute to this disorder. Since the onset of IBD is often during infancy, in the present study, the serum values of a large panel of cytokines and chemokines in pediatric patients (<18 years; n=26) were compared with age-matched controls (n=37). While elevations in the serum level of several proinflammatory and immune regulating cytokines were confirmed, such as interleukin (IL)-1β, IL-5, IL-7, interferon (IFN)-γ-inducible protein-10, IL-16, cutaneous T-cell-attracting chemokine, leukemia inhibitory factor, monokine induced by γ-IFN, IFN-α2 and IFN-γ, notably decreased levels of IL-2, IL-17 and macrophage inhibitory protein-1β were also observed. Therefore, while a number of proinflammatory cytokines exhibit increased levels in IBD patients, pediatric IBD patients may also exhibit certain aspects of a reduced immunological response.

VL - 9 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26136934?dopt=Abstract ER - TY - JOUR T1 - Population genetic differentiation of height and body mass index across Europe. JF - Nat Genet Y1 - 2015 A1 - Robinson, Matthew R A1 - Hemani, Gibran A1 - Medina-Gomez, Carolina A1 - Mezzavilla, Massimo A1 - Esko, Tõnu A1 - Shakhbazov, Konstantin A1 - Powell, Joseph E A1 - Vinkhuyzen, Anna A1 - Berndt, Sonja I A1 - Gustafsson, Stefan A1 - Justice, Anne E A1 - Kahali, Bratati A1 - Locke, Adam E A1 - Pers, Tune H A1 - Vedantam, Sailaja A1 - Wood, Andrew R A1 - van Rheenen, Wouter A1 - Andreassen, Ole A A1 - Gasparini, Paolo A1 - Metspalu, Andres A1 - Berg, Leonard H van den A1 - Veldink, Jan H A1 - Rivadeneira, Fernando A1 - Werge, Thomas M A1 - Abecasis, Goncalo R A1 - Boomsma, Dorret I A1 - Chasman, Daniel I A1 - de Geus, Eco J C A1 - Frayling, Timothy M A1 - Hirschhorn, Joel N A1 - Hottenga, Jouke Jan A1 - Ingelsson, Erik A1 - Loos, Ruth J F A1 - Magnusson, Patrik K E A1 - Martin, Nicholas G A1 - Montgomery, Grant W A1 - North, Kari E A1 - Pedersen, Nancy L A1 - Spector, Timothy D A1 - Speliotes, Elizabeth K A1 - Goddard, Michael E A1 - Yang, Jian A1 - Visscher, Peter M AB -

Across-nation differences in the mean values for complex traits are common, but the reasons for these differences are unknown. Here we find that many independent loci contribute to population genetic differences in height and body mass index (BMI) in 9,416 individuals across 14 European countries. Using discovery data on over 250,000 individuals and unbiased effect size estimates from 17,500 sibling pairs, we estimate that 24% (95% credible interval (CI) = 9%, 41%) and 8% (95% CI = 4%, 16%) of the captured additive genetic variance for height and BMI, respectively, reflect population genetic differences. Population genetic divergence differed significantly from that in a null model (height, P < 3.94 × 10(-8); BMI, P < 5.95 × 10(-4)), and we find an among-population genetic correlation for tall and slender individuals (r = -0.80, 95% CI = -0.95, -0.60), consistent with correlated selection for both phenotypes. Observed differences in height among populations reflected the predicted genetic means (r = 0.51; P < 0.001), but environmental differences across Europe masked genetic differentiation for BMI (P < 0.58).

VL - 47 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26366552?dopt=Abstract ER - TY - JOUR T1 - R705H mutation of MYH9 is associated with MYH9-related disease and not only with non-syndromic deafness DFNA17. JF - Clin Genet Y1 - 2015 A1 - Verver, E A1 - Pecci, A A1 - De Rocco, D A1 - Ryhänen, S A1 - Barozzi, S A1 - Kunst, H A1 - Topsakal, V A1 - Savoia, A AB -

MYH9-related disease (MYH9-RD) is a rare autosomal dominant disease caused by mutation of MYH9, the gene encoding for the heavy chain of non-muscle myosin IIA (NMMHC-IIA). MYH9-RD patients have macrothrombocytopenia and granulocyte inclusions (pathognomonic sign of the disease) containing wild-type and mutant NMMHC-IIA. During life they might develop sensorineural hearing loss, cataract, glomerulonephritis, and elevation of liver enzymes. One of the MYH9 mutations, p.R705H, was previously reported to be associated with DFNA17, an autosomal dominant non-syndromic sensorineural hearing loss without any other features associated. We identified the same mutation in two unrelated families, whose four affected individuals had not only hearing impairment but also thrombocytopenia, giant platelets, leukocyte inclusions, as well as mild to moderate elevation of some liver enzymes. Our data suggest that DFNA17 should not be a separate genetic entity but part of the wide phenotypic spectrum of MYH9-RD characterized by congenital hematological manifestations and variable penetrance and expressivity of the extra-hematological features.

VL - 88 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24890873?dopt=Abstract ER - TY - JOUR T1 - Rare coding variants and X-linked loci associated with age at menarche. JF - Nat Commun Y1 - 2015 A1 - Lunetta, Kathryn L A1 - Day, Felix R A1 - Sulem, Patrick A1 - Ruth, Katherine S A1 - Tung, Joyce Y A1 - Hinds, David A A1 - Esko, Tõnu A1 - Elks, Cathy E A1 - Altmaier, Elisabeth A1 - He, Chunyan A1 - Huffman, Jennifer E A1 - Mihailov, Evelin A1 - Porcu, Eleonora A1 - Robino, Antonietta A1 - Rose, Lynda M A1 - Schick, Ursula M A1 - Stolk, Lisette A1 - Teumer, Alexander A1 - Thompson, Deborah J A1 - Traglia, Michela A1 - Wang, Carol A A1 - Yerges-Armstrong, Laura M A1 - Antoniou, Antonis C A1 - Barbieri, Caterina A1 - Coviello, Andrea D A1 - Cucca, Francesco A1 - Demerath, Ellen W A1 - Dunning, Alison M A1 - Gandin, Ilaria A1 - Grove, Megan L A1 - Gudbjartsson, Daniel F A1 - Hocking, Lynne J A1 - Hofman, Albert A1 - Huang, Jinyan A1 - Jackson, Rebecca D A1 - Karasik, David A1 - Kriebel, Jennifer A1 - Lange, Ethan M A1 - Lange, Leslie A A1 - Langenberg, Claudia A1 - Li, Xin A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Morrison, Alanna C A1 - Padmanabhan, Sandosh A1 - Pirie, Ailith A1 - Polasek, Ozren A1 - Porteous, David A1 - Reiner, Alex P A1 - Rivadeneira, Fernando A1 - Rudan, Igor A1 - Sala, Cinzia F A1 - Schlessinger, David A1 - Scott, Robert A A1 - Stöckl, Doris A1 - Visser, Jenny A A1 - Völker, Uwe A1 - Vozzi, Diego A1 - Wilson, James G A1 - Zygmunt, Marek A1 - Boerwinkle, Eric A1 - Buring, Julie E A1 - Crisponi, Laura A1 - Easton, Douglas F A1 - Hayward, Caroline A1 - Hu, Frank B A1 - Liu, Simin A1 - Metspalu, Andres A1 - Pennell, Craig E A1 - Ridker, Paul M A1 - Strauch, Konstantin A1 - Streeten, Elizabeth A A1 - Toniolo, Daniela A1 - Uitterlinden, André G A1 - Ulivi, Sheila A1 - Völzke, Henry A1 - Wareham, Nicholas J A1 - Wellons, Melissa A1 - Franceschini, Nora A1 - Chasman, Daniel I A1 - Thorsteinsdottir, Unnur A1 - Murray, Anna A1 - Stefansson, Kari A1 - Murabito, Joanne M A1 - Ong, Ken K A1 - Perry, John R B AB -

More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 × 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10(-13)) and FAAH2 (rs5914101, P=4.9 × 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.

VL - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26239645?dopt=Abstract ER - TY - JOUR T1 - Two‑gene mutation in a single patient: Biochemical and functional analysis for a correct interpretation of exome results. JF - Mol Med Rep Y1 - 2015 A1 - Bianco, Anna Monica A1 - Faletra, Flavio A1 - Vozzi, Diego A1 - Girardelli, Martina A1 - Knowles, Alessandra A1 - Tommasini, Alberto A1 - Zauli, Giorgio A1 - Marcuzzi, Annalisa AB -

Next-generation sequencing (NGS) has generated a large amount of sequence data with the requirement of frequent critical revisions of reported mutations. This innovative tool has proved to be effective in detecting pathogenic mutations; however, it requires a certain degree of experience to identify incidental findings. In the present study, whole exome sequencing analysis was performed for the molecular diagnosis and correct genotype/phenotype correlation between parents and a patient presenting with an atypical phenotype. In addition, mevalonic acid quantification and frequency analysis of detected variants in public databases and X‑chromosome inactivation (XCI) studies on the patient's mother were performed. V377I as well as the S135L mutations were identified on the mevalonate kinase deficiency gene and the levels of mevalonic acid in the patient were 5,496 µg/ml. A D59G variation, reported in ESP6500 in two healthy individuals, was found on the Martin Probst syndrome gene (RAB40AL). Based on XCI studies on the patient's mother, it is likely that RAB40AL escapes XCI, while still remaining balanced. In conclusion, the results of the present study indicated that the Martin Probst syndrome is an X‑linked condition, which is probably not caused by RAB40AL mutations. Although NGS is a powerful tool to identify pathogenic mutations, the analysis of genetic data requires expert critical revision of all detected variants.

VL - 12 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26300074?dopt=Abstract ER - TY - JOUR T1 - Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. JF - Haematologica Y1 - 2014 A1 - Noris, Patrizia A1 - Schlegel, Nicole A1 - Klersy, Catherine A1 - Heller, Paula G A1 - Civaschi, Elisa A1 - Pujol-Moix, Núria A1 - Fabris, Fabrizio A1 - Favier, Rémi A1 - Gresele, Paolo A1 - Latger-Cannard, Véronique A1 - Cuker, Adam A1 - Nurden, Paquita A1 - Greinacher, Andreas A1 - Cattaneo, Marco A1 - De Candia, Erica A1 - Pecci, Alessandro A1 - Hurtaud-Roux, Marie-Françoise A1 - Glembotsky, Ana C A1 - Muñiz-Diaz, Eduardo A1 - Randi, Maria Luigia A1 - Trillot, Nathalie A1 - Bury, Loredana A1 - Lecompte, Thomas A1 - Marconi, Caterina A1 - Savoia, Anna A1 - Balduini, Carlo L A1 - Bayart, Sophie A1 - Bauters, Anne A1 - Benabdallah-Guedira, Schéhérazade A1 - Boehlen, Françoise A1 - Borg, Jeanne-Yvonne A1 - Bottega, Roberta A1 - Bussel, James A1 - De Rocco, Daniela A1 - de Maistre, Emmanuel A1 - Faleschini, Michela A1 - Falcinelli, Emanuela A1 - Ferrari, Silvia A1 - Ferster, Alina A1 - Fierro, Tiziana A1 - Fleury, Dominique A1 - Fontana, Pierre A1 - James, Chloé A1 - Lanza, Francois A1 - Le Cam Duchez, Véronique A1 - Loffredo, Giuseppe A1 - Magini, Pamela A1 - Martin-Coignard, Dominique A1 - Menard, Fanny A1 - Mercier, Sandra A1 - Mezzasoma, Annamaria A1 - Minuz, Pietro A1 - Nichele, Ilaria A1 - Notarangelo, Lucia D A1 - Pippucci, Tommaso A1 - Podda, Gian Marco A1 - Pouymayou, Catherine A1 - Rigouzzo, Agnes A1 - Royer, Bruno A1 - Sie, Pierre A1 - Siguret, Virginie A1 - Trichet, Catherine A1 - Tucci, Alessandra A1 - Saposnik, Béatrice A1 - Veneri, Dino KW - Adult KW - Female KW - Humans KW - Infant, Newborn KW - Pregnancy KW - Pregnancy Complications, Hematologic KW - Retrospective Studies KW - Thrombocytopenia KW - Young Adult AB -

Pregnancy in women with inherited thrombocytopenias is a major matter of concern as both the mothers and the newborns are potentially at risk of bleeding. However, medical management of this condition cannot be based on evidence because of the lack of consistent information in the literature. To advance knowledge on this matter, we performed a multicentric, retrospective study evaluating 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Neither the degree of thrombocytopenia nor the severity of bleeding tendency worsened during pregnancy and the course of pregnancy did not differ from that of healthy subjects in terms of miscarriages, fetal bleeding and pre-term births. The degree of thrombocytopenia in the babies was similar to that in the mother. Only 7 of 156 affected newborns had delivery-related bleeding, but 2 of them died of cerebral hemorrhage. The frequency of delivery-related maternal bleeding ranged from 6.8% to 14.2% depending on the definition of abnormal blood loss, suggesting that the risk of abnormal blood loss was increased with respect to the general population. However, no mother died or had to undergo hysterectomy to arrest bleeding. The search for parameters predicting delivery-related bleeding in the mother suggested that hemorrhages requiring blood transfusion were more frequent in women with history of severe bleedings before pregnancy and with platelet count at delivery below 50 × 10(9)/L.

VL - 99 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24763399?dopt=Abstract ER - TY - JOUR T1 - Association analysis of bitter receptor genes in five isolated populations identifies a significant correlation between TAS2R43 variants and coffee liking. JF - PLoS One Y1 - 2014 A1 - Pirastu, Nicola A1 - Kooyman, Maarten A1 - Traglia, Michela A1 - Robino, Antonietta A1 - Willems, Sara M A1 - Pistis, Giorgio A1 - d'Adamo, Pio A1 - Amin, Najaf A1 - D'Eustacchio, Angela A1 - Navarini, Luciano A1 - Sala, Cinzia A1 - Karssen, Lennart C A1 - van Duijn, Cornelia A1 - Toniolo, Daniela A1 - Gasparini, Paolo KW - Coffee KW - Genetic Association Studies KW - Humans KW - Polymorphism, Single Nucleotide KW - Receptors, G-Protein-Coupled KW - Taste AB -

Coffee, one of the most popular beverages in the world, contains many different physiologically active compounds with a potential impact on people's health. Despite the recent attention given to the genetic basis of its consumption, very little has been done in understanding genes influencing coffee preference among different individuals. Given its markedly bitter taste, we decided to verify if bitter receptor genes (TAS2Rs) variants affect coffee liking. In this light, 4066 people from different parts of Europe and Central Asia filled in a field questionnaire on coffee liking. They have been consequently recruited and included in the study. Eighty-eight SNPs covering the 25 TAS2R genes were selected from the available imputed ones and used to run association analysis for coffee liking. A significant association was detected with three SNP: one synonymous and two functional variants (W35S and H212R) on the TAS2R43 gene. Both variants have been shown to greatly reduce in vitro protein activity. Surprisingly the wild type allele, which corresponds to the functional form of the protein, is associated to higher liking of coffee. Since the hTAS2R43 receptor is sensible to caffeine, we verified if the detected variants produced differences in caffeine bitter perception on a subsample of people coming from the FVG cohort. We found a significant association between differences in caffeine perception and the H212R variant but not with the W35S, which suggests that the effect of the TAS2R43 gene on coffee liking is mediated by caffeine and in particular by the H212R variant. No other significant association was found with other TAS2R genes. In conclusion, the present study opens new perspectives in the understanding of coffee liking. Further studies are needed to clarify the role of the TAS2R43 gene in coffee hedonics and to identify which other genes and pathways are involved in its genetics.

VL - 9 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24647340?dopt=Abstract ER - TY - JOUR T1 - Block of the mevalonate pathway triggers oxidative and inflammatory molecular mechanisms modulated by exogenous isoprenoid compounds. JF - Int J Mol Sci Y1 - 2014 A1 - Tricarico, Paola Maura A1 - Kleiner, Giulio A1 - Valencic, Erica A1 - Campisciano, Giuseppina A1 - Girardelli, Martina A1 - Crovella, Sergio A1 - Knowles, Alessandra A1 - Marcuzzi, Annalisa KW - Animals KW - Apoptosis KW - Carotenoids KW - Carrier Proteins KW - Cell Line KW - Cytokines KW - Diterpenes KW - Humans KW - Mevalonate Kinase Deficiency KW - Mevalonic Acid KW - Mice KW - Mitochondria KW - Nitric Oxide KW - Phytol KW - Terpenes AB -

Deregulation of the mevalonate pathway is known to be involved in a number of diseases that exhibit a systemic inflammatory phenotype and often neurological involvements, as seen in patients suffering from a rare disease called mevalonate kinase deficiency (MKD). One of the molecular mechanisms underlying this pathology could depend on the shortage of isoprenoid compounds and the subsequent mitochondrial damage, leading to oxidative stress and pro-inflammatory cytokines' release. Moreover, it has been demonstrated that cellular death results from the balance between apoptosis and pyroptosis, both driven by mitochondrial damage and the molecular platform inflammasome. In order to rescue the deregulated pathway and decrease inflammatory markers, exogenous isoprenoid compounds were administered to a biochemical model of MKD obtained treating a murine monocytic cell line with a compound able to block the mevalonate pathway, plus an inflammatory stimulus. Our results show that isoprenoids acted in different ways, mainly increasing the expression of the evaluated markers [apoptosis, mitochondrial dysfunction, nucleotide-binding oligomerization-domain protein-like receptors 3 (NALP3), cytokines and nitric oxide (NO)]. Our findings confirm the hypothesis that inflammation is triggered, at least partially, by the shortage of isoprenoids. Moreover, although further studies are necessary, the achieved results suggest a possible role for exogenous isoprenoids in the treatment of MKD.

VL - 15 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24758928?dopt=Abstract ER - TY - JOUR T1 - Common variants in UMOD associate with urinary uromodulin levels: a meta-analysis. JF - J Am Soc Nephrol Y1 - 2014 A1 - Olden, Matthias A1 - Corre, Tanguy A1 - Hayward, Caroline A1 - Toniolo, Daniela A1 - Ulivi, Sheila A1 - Gasparini, Paolo A1 - Pistis, Giorgio A1 - Hwang, Shih-Jen A1 - Bergmann, Sven A1 - Campbell, Harry A1 - Cocca, Massimiliano A1 - Gandin, Ilaria A1 - Girotto, Giorgia A1 - Glaudemans, Bob A1 - Hastie, Nicholas D A1 - Loffing, Johannes A1 - Polasek, Ozren A1 - Rampoldi, Luca A1 - Rudan, Igor A1 - Sala, Cinzia A1 - Traglia, Michela A1 - Vollenweider, Peter A1 - Vuckovic, Dragana A1 - Youhanna, Sonia A1 - Weber, Julien A1 - Wright, Alan F A1 - Kutalik, Zoltán A1 - Bochud, Murielle A1 - Fox, Caroline S A1 - Devuyst, Olivier KW - Creatinine KW - European Continental Ancestry Group KW - Genetic Variation KW - Humans KW - Polymorphism, Single Nucleotide KW - Uromodulin AB -

Uromodulin is expressed exclusively in the thick ascending limb and is the most abundant protein excreted in normal urine. Variants in UMOD, which encodes uromodulin, are associated with renal function, and urinary uromodulin levels may be a biomarker for kidney disease. However, the genetic factors regulating uromodulin excretion are unknown. We conducted a meta-analysis of urinary uromodulin levels to identify associated common genetic variants in the general population. We included 10,884 individuals of European descent from three genetic isolates and three urban cohorts. Each study measured uromodulin indexed to creatinine and conducted linear regression analysis of approximately 2.5 million single nucleotide polymorphisms using an additive model. We also tested whether variants in genes expressed in the thick ascending limb associate with uromodulin levels. rs12917707, located near UMOD and previously associated with renal function and CKD, had the strongest association with urinary uromodulin levels (P<0.001). In all cohorts, carriers of a G allele of this variant had higher uromodulin levels than noncarriers did (geometric means 10.24, 14.05, and 17.67 μg/g creatinine for zero, one, or two copies of the G allele). rs12446492 in the adjacent gene PDILT (protein disulfide isomerase-like, testis expressed) also reached genome-wide significance (P<0.001). Regarding genes expressed in the thick ascending limb, variants in KCNJ1, SORL1, and CAB39 associated with urinary uromodulin levels. These data indicate that common variants in the UMOD promoter region may influence urinary uromodulin levels. They also provide insights into uromodulin biology and the association of UMOD variants with renal function.

VL - 25 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24578125?dopt=Abstract ER - TY - JOUR T1 - DNA mismatch repair gene MSH6 implicated in determining age at natural menopause. JF - Hum Mol Genet Y1 - 2014 A1 - Perry, John R B A1 - Hsu, Yi-Hsiang A1 - Chasman, Daniel I A1 - Johnson, Andrew D A1 - Elks, Cathy A1 - Albrecht, Eva A1 - Andrulis, Irene L A1 - Beesley, Jonathan A1 - Berenson, Gerald S A1 - Bergmann, Sven A1 - Bojesen, Stig E A1 - Bolla, Manjeet K A1 - Brown, Judith A1 - Buring, Julie E A1 - Campbell, Harry A1 - Chang-Claude, Jenny A1 - Chenevix-Trench, Georgia A1 - Corre, Tanguy A1 - Couch, Fergus J A1 - Cox, Angela A1 - Czene, Kamila A1 - d'Adamo, Adamo Pio A1 - Davies, Gail A1 - Deary, Ian J A1 - Dennis, Joe A1 - Easton, Douglas F A1 - Engelhardt, Ellen G A1 - Eriksson, Johan G A1 - Esko, Tõnu A1 - Fasching, Peter A A1 - Figueroa, Jonine D A1 - Flyger, Henrik A1 - Fraser, Abigail A1 - Garcia-Closas, Montse A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Giles, Graham A1 - Guenel, Pascal A1 - Hägg, Sara A1 - Hall, Per A1 - Hayward, Caroline A1 - Hopper, John A1 - Ingelsson, Erik A1 - Kardia, Sharon L R A1 - Kasiman, Katherine A1 - Knight, Julia A A1 - Lahti, Jari A1 - Lawlor, Debbie A A1 - Magnusson, Patrik K E A1 - Margolin, Sara A1 - Marsh, Julie A A1 - Metspalu, Andres A1 - Olson, Janet E A1 - Pennell, Craig E A1 - Polasek, Ozren A1 - Rahman, Iffat A1 - Ridker, Paul M A1 - Robino, Antonietta A1 - Rudan, Igor A1 - Rudolph, Anja A1 - Salumets, Andres A1 - Schmidt, Marjanka K A1 - Schoemaker, Minouk J A1 - Smith, Erin N A1 - Smith, Jennifer A A1 - Southey, Melissa A1 - Stöckl, Doris A1 - Swerdlow, Anthony J A1 - Thompson, Deborah J A1 - Truong, Therese A1 - Ulivi, Sheila A1 - Waldenberger, Melanie A1 - Wang, Qin A1 - Wild, Sarah A1 - Wilson, James F A1 - Wright, Alan F A1 - Zgaga, Lina A1 - Ong, Ken K A1 - Murabito, Joanne M A1 - Karasik, David A1 - Murray, Anna KW - Age Factors KW - DNA-Binding Proteins KW - Female KW - Genome-Wide Association Study KW - Humans KW - Menopause KW - Polymorphism, Single Nucleotide AB -

The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to ∼50% of the variation in both age at menarche and menopause, but to date the known genes explain <15% of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using genome-wide complex trait analysis. However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P = 1.9 × 10(-9)), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertility.

VL - 23 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24357391?dopt=Abstract ER - TY - JOUR T1 - Experience from a single paediatric transplant centre with identification of some protective and risk factors concerning the development of hepatic veno-occlusive disease in children after allogeneic hematopoietic stem cell transplant. JF - Int J Hematol Y1 - 2014 A1 - Maximova, N A1 - Ferrara, G A1 - Minute, M A1 - Pizzol, A A1 - Kiren, V A1 - Montico, M A1 - Gregori, M A1 - Tamaro, P KW - Adolescent KW - Child KW - Child, Preschool KW - Female KW - Hematopoietic Stem Cell Transplantation KW - Hepatic Veno-Occlusive Disease KW - Humans KW - Infant KW - Infant, Newborn KW - Male KW - Mortality KW - Retrospective Studies KW - Risk Factors KW - Transplantation, Homologous KW - Young Adult AB -

Hepatic veno-occlusive disease (VOD) is a frequent and severe complication of hematopoietic stem cell transplantation (HSCT) affecting 9.6-17.3 % of cases. 200 HSCT, performed between January 1995 and March 2013 in our Paediatric HSCT Centre in Trieste, were retrospectively analysed to evaluate the frequency of VOD and to identify the associated risk factors. The frequency of VOD according to the Seattle criteria was 17 %, within the range reported in literature. The mortality rate was 37.5 % (75 out of 200 transplantations) in the general population and 73.5 % (25 out of 34) in VOD patients (p < 0.05). Veno-occlusive disease significantly decreased from 38 % (1995-2000) to 8 % (2007-2013) p < 0.05. Univariate and multivariate analyses identified sepsis and pre-transplant ferritin levels above 1000 ng/ml as two significant risk factors for VOD, while the use of tacrolimus appeared to be associated with a lower VOD risk. Veno-occlusive disease still remains an important cause of transplant-related mortality even if it appears to have decreased over the last few years.

VL - 99 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24715523?dopt=Abstract ER - TY - JOUR T1 - From tube to breast: the bridging role of semi-demand breastfeeding. JF - J Hum Lact Y1 - 2014 A1 - Davanzo, Riccardo A1 - Strajn, Tamara A1 - Kennedy, Jacqueline A1 - Crocetta, Anna A1 - De Cunto, Angela AB -

Determination of the optimal timing of breastfeeding initiation for preterm infants is still a challenge for health professionals. Often unjustified delays and restrictions of breastfeeding occur due to non-evidence-based current opinions about preterm infants' feeding capacity. Semi-demand feeding has been proposed for preterm infants during the transition from scheduled to full demand feeding, to promote the establishment of self-regulated oral feeding. Although semi-demand feeding has been shown to be safe and effective in reducing time to reaching oral feeding, the implementation of this feeding pattern for preterm infants in the neonatal intensive care unit (NICU) is still limited. We developed a protocol for the application of semi-demand feeding in preterm infants based on the existing knowledge of preterm infant neurodevelopment and NICU organization and staff experience. The protocol's aim is to attain successful transition from tube feeding to breastfeeding. In this article, we describe the protocol used in the neonatal unit of the Maternal and Child Health Institute of Trieste, a third level care center in northeastern Italy.

VL - 30 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25172892?dopt=Abstract ER - TY - JOUR T1 - Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. JF - Nat Genet Y1 - 2014 A1 - Arking, Dan E A1 - Pulit, Sara L A1 - Crotti, Lia A1 - van der Harst, Pim A1 - Munroe, Patricia B A1 - Koopmann, Tamara T A1 - Sotoodehnia, Nona A1 - Rossin, Elizabeth J A1 - Morley, Michael A1 - Wang, Xinchen A1 - Johnson, Andrew D A1 - Lundby, Alicia A1 - Gudbjartsson, Daniel F A1 - Noseworthy, Peter A A1 - Eijgelsheim, Mark A1 - Bradford, Yuki A1 - Tarasov, Kirill V A1 - Dörr, Marcus A1 - Müller-Nurasyid, Martina A1 - Lahtinen, Annukka M A1 - Nolte, Ilja M A1 - Smith, Albert Vernon A1 - Bis, Joshua C A1 - Isaacs, Aaron A1 - Newhouse, Stephen J A1 - Evans, Daniel S A1 - Post, Wendy S A1 - Waggott, Daryl A1 - Lyytikäinen, Leo-Pekka A1 - Hicks, Andrew A A1 - Eisele, Lewin A1 - Ellinghaus, David A1 - Hayward, Caroline A1 - Navarro, Pau A1 - Ulivi, Sheila A1 - Tanaka, Toshiko A1 - Tester, David J A1 - Chatel, Stéphanie A1 - Gustafsson, Stefan A1 - Kumari, Meena A1 - Morris, Richard W A1 - Naluai, Åsa T A1 - Padmanabhan, Sandosh A1 - Kluttig, Alexander A1 - Strohmer, Bernhard A1 - Panayiotou, Andrie G A1 - Torres, Maria A1 - Knoflach, Michael A1 - Hubacek, Jaroslav A A1 - Slowikowski, Kamil A1 - Raychaudhuri, Soumya A1 - Kumar, Runjun D A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Shuldiner, Alan R A1 - Alonso, Alvaro A1 - Bader, Joel S A1 - Ehret, Georg A1 - Huang, Hailiang A1 - Kao, W H Linda A1 - Strait, James B A1 - Macfarlane, Peter W A1 - Brown, Morris A1 - Caulfield, Mark J A1 - Samani, Nilesh J A1 - Kronenberg, Florian A1 - Willeit, Johann A1 - Smith, J Gustav A1 - Greiser, Karin H A1 - Meyer Zu Schwabedissen, Henriette A1 - Werdan, Karl A1 - Carella, Massimo A1 - Zelante, Leopoldo A1 - Heckbert, Susan R A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Kolcic, Ivana A1 - Polasek, Ozren A1 - Wright, Alan F A1 - Griffin, Maura A1 - Daly, Mark J A1 - Arnar, David O A1 - Holm, Hilma A1 - Thorsteinsdottir, Unnur A1 - Denny, Joshua C A1 - Roden, Dan M A1 - Zuvich, Rebecca L A1 - Emilsson, Valur A1 - Plump, Andrew S A1 - Larson, Martin G A1 - O'Donnell, Christopher J A1 - Yin, Xiaoyan A1 - Bobbo, Marco A1 - d'Adamo, Adamo P A1 - Iorio, Annamaria A1 - Sinagra, Gianfranco A1 - Carracedo, Angel A1 - Cummings, Steven R A1 - Nalls, Michael A A1 - Jula, Antti A1 - Kontula, Kimmo K A1 - Marjamaa, Annukka A1 - Oikarinen, Lasse A1 - Perola, Markus A1 - Porthan, Kimmo A1 - Erbel, Raimund A1 - Hoffmann, Per A1 - Jöckel, Karl-Heinz A1 - Kälsch, Hagen A1 - Nöthen, Markus M A1 - den Hoed, Marcel A1 - Loos, Ruth J F A1 - Thelle, Dag S A1 - Gieger, Christian A1 - Meitinger, Thomas A1 - Perz, Siegfried A1 - Peters, Annette A1 - Prucha, Hanna A1 - Sinner, Moritz F A1 - Waldenberger, Melanie A1 - de Boer, Rudolf A A1 - Franke, Lude A1 - van der Vleuten, Pieter A A1 - Beckmann, Britt Maria A1 - Martens, Eimo A1 - Bardai, Abdennasser A1 - Hofman, Nynke A1 - Wilde, Arthur A M A1 - Behr, Elijah R A1 - Dalageorgou, Chrysoula A1 - Giudicessi, John R A1 - Medeiros-Domingo, Argelia A1 - Barc, Julien A1 - Kyndt, Florence A1 - Probst, Vincent A1 - Ghidoni, Alice A1 - Insolia, Roberto A1 - Hamilton, Robert M A1 - Scherer, Stephen W A1 - Brandimarto, Jeffrey A1 - Margulies, Kenneth A1 - Moravec, Christine E A1 - del Greco M, Fabiola A1 - Fuchsberger, Christian A1 - O'Connell, Jeffrey R A1 - Lee, Wai K A1 - Watt, Graham C M A1 - Campbell, Harry A1 - Wild, Sarah H A1 - El Mokhtari, Nour E A1 - Frey, Norbert A1 - Asselbergs, Folkert W A1 - Mateo Leach, Irene A1 - Navis, Gerjan A1 - van den Berg, Maarten P A1 - van Veldhuisen, Dirk J A1 - Kellis, Manolis A1 - Krijthe, Bouwe P A1 - Franco, Oscar H A1 - Hofman, Albert A1 - Kors, Jan A A1 - Uitterlinden, André G A1 - Witteman, Jacqueline C M A1 - Kedenko, Lyudmyla A1 - Lamina, Claudia A1 - Oostra, Ben A A1 - Abecasis, Goncalo R A1 - Lakatta, Edward G A1 - Mulas, Antonella A1 - Orru, Marco A1 - Schlessinger, David A1 - Uda, Manuela A1 - Markus, Marcello R P A1 - Völker, Uwe A1 - Snieder, Harold A1 - Spector, Timothy D A1 - Arnlöv, Johan A1 - Lind, Lars A1 - Sundström, Johan A1 - Syvänen, Ann-Christine A1 - Kivimaki, Mika A1 - Kähönen, Mika A1 - Mononen, Nina A1 - Raitakari, Olli T A1 - Viikari, Jorma S A1 - Adamkova, Vera A1 - Kiechl, Stefan A1 - Brion, Maria A1 - Nicolaides, Andrew N A1 - Paulweber, Bernhard A1 - Haerting, Johannes A1 - Dominiczak, Anna F A1 - Nyberg, Fredrik A1 - Whincup, Peter H A1 - Hingorani, Aroon D A1 - Schott, Jean-Jacques A1 - Bezzina, Connie R A1 - Ingelsson, Erik A1 - Ferrucci, Luigi A1 - Gasparini, Paolo A1 - Wilson, James F A1 - Rudan, Igor A1 - Franke, Andre A1 - Mühleisen, Thomas W A1 - Pramstaller, Peter P A1 - Lehtimäki, Terho J A1 - Paterson, Andrew D A1 - Parsa, Afshin A1 - Liu, Yongmei A1 - van Duijn, Cornelia M A1 - Siscovick, David S A1 - Gudnason, Vilmundur A1 - Jamshidi, Yalda A1 - Salomaa, Veikko A1 - Felix, Stephan B A1 - Sanna, Serena A1 - Ritchie, Marylyn D A1 - Stricker, Bruno H A1 - Stefansson, Kari A1 - Boyer, Laurie A A1 - Cappola, Thomas P A1 - Olsen, Jesper V A1 - Lage, Kasper A1 - Schwartz, Peter J A1 - Kääb, Stefan A1 - Chakravarti, Aravinda A1 - Ackerman, Michael J A1 - Pfeufer, Arne A1 - de Bakker, Paul I W A1 - Newton-Cheh, Christopher KW - Adult KW - Aged KW - Arrhythmias, Cardiac KW - Calcium Signaling KW - Death, Sudden, Cardiac KW - Electrocardiography KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Heart Ventricles KW - Humans KW - Long QT Syndrome KW - Male KW - Middle Aged KW - Myocardium KW - Polymorphism, Single Nucleotide AB -

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

VL - 46 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24952745?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty. JF - Hum Mol Genet Y1 - 2014 A1 - Cousminer, Diana L A1 - Stergiakouli, Evangelia A1 - Berry, Diane J A1 - Ang, Wei A1 - Groen-Blokhuis, Maria M A1 - Körner, Antje A1 - Siitonen, Niina A1 - Ntalla, Ioanna A1 - Marinelli, Marcella A1 - Perry, John R B A1 - Kettunen, Johannes A1 - Jansen, Rick A1 - Surakka, Ida A1 - Timpson, Nicholas J A1 - Ring, Susan A1 - McMahon, George A1 - Power, Chris A1 - Wang, Carol A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Lehtimäki, Terho A1 - Middeldorp, Christel M A1 - Hulshoff Pol, Hilleke E A1 - Neef, Madlen A1 - Weise, Sebastian A1 - Pahkala, Katja A1 - Niinikoski, Harri A1 - Zeggini, Eleftheria A1 - Panoutsopoulou, Kalliope A1 - Bustamante, Mariona A1 - Penninx, Brenda W J H A1 - Murabito, Joanne A1 - Torrent, Maties A1 - Dedoussis, George V A1 - Kiess, Wieland A1 - Boomsma, Dorret I A1 - Pennell, Craig E A1 - Raitakari, Olli T A1 - Hyppönen, Elina A1 - Davey Smith, George A1 - Ripatti, Samuli A1 - McCarthy, Mark I A1 - Widen, Elisabeth AB -

Little is known about genes regulating male puberty. Further, while many identified pubertal timing variants associate with age at menarche, a late manifestation of puberty, and body mass, little is known about these variants' relationship to pubertal initiation or tempo. To address these questions, we performed genome-wide association meta-analysis in over 11 000 European samples with data on early pubertal traits, male genital and female breast development, measured by the Tanner scale. We report the first genome-wide significant locus for male sexual development upstream of myocardin-like 2 (MKL2) (P = 8.9 × 10(-9)), a menarche locus tagging a developmental pathway linking earlier puberty with reduced pubertal growth (P = 4.6 × 10(-5)) and short adult stature (p = 7.5 × 10(-6)) in both males and females. Furthermore, our results indicate that a proportion of menarche loci are important for pubertal initiation in both sexes. Consistent with epidemiological correlations between increased prepubertal body mass and earlier pubertal timing in girls, body mass index (BMI)-increasing alleles correlated with earlier breast development. In boys, some BMI-increasing alleles associated with earlier, and others with delayed, sexual development; these genetic results mimic the controversy in epidemiological studies, some of which show opposing correlations between prepubertal BMI and male puberty. Our results contribute to our understanding of the pubertal initiation program in both sexes and indicate that although mechanisms regulating pubertal onset in males and females may largely be shared, the relationship between body mass and pubertal timing in boys may be complex and requires further genetic studies.

VL - 23 IS - 16 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24770850?dopt=Abstract ER - TY - JOUR T1 - Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. JF - Lancet Y1 - 2014 A1 - Murray, Christopher J L A1 - Ortblad, Katrina F A1 - Guinovart, Caterina A1 - Lim, Stephen S A1 - Wolock, Timothy M A1 - Roberts, D Allen A1 - Dansereau, Emily A A1 - Graetz, Nicholas A1 - Barber, Ryan M A1 - Brown, Jonathan C A1 - Wang, Haidong A1 - Duber, Herbert C A1 - Naghavi, Mohsen A1 - Dicker, Daniel A1 - Dandona, Lalit A1 - Salomon, Joshua A A1 - Heuton, Kyle R A1 - Foreman, Kyle A1 - Phillips, David E A1 - Fleming, Thomas D A1 - Flaxman, Abraham D A1 - Phillips, Bryan K A1 - Johnson, Elizabeth K A1 - Coggeshall, Megan S A1 - Abd-Allah, Foad A1 - Abera, Semaw Ferede A1 - Abraham, Jerry P A1 - Abubakar, Ibrahim A1 - Abu-Raddad, Laith J A1 - Abu-Rmeileh, Niveen Me A1 - Achoki, Tom A1 - Adeyemo, Austine Olufemi A1 - Adou, Arsène Kouablan A1 - Adsuar, José C A1 - Agardh, Emilie Elisabet A1 - Akena, Dickens A1 - Al Kahbouri, Mazin J A1 - Alasfoor, Deena A1 - Albittar, Mohammed I A1 - Alcalá-Cerra, Gabriel A1 - Alegretti, Miguel Angel A1 - Alemu, Zewdie Aderaw A1 - Alfonso-Cristancho, Rafael A1 - Alhabib, Samia A1 - Ali, Raghib A1 - Alla, François A1 - Allen, Peter J A1 - Alsharif, Ubai A1 - Alvarez, Elena A1 - Alvis-Guzmán, Nelson A1 - Amankwaa, Adansi A A1 - Amare, Azmeraw T A1 - Amini, Hassan A1 - Ammar, Walid A1 - Anderson, Benjamin O A1 - Antonio, Carl Abelardo T A1 - Anwari, Palwasha A1 - Arnlöv, Johan A1 - Arsenijevic, Valentina S Arsic A1 - Artaman, Ali A1 - Asghar, Rana J A1 - Assadi, Reza A1 - Atkins, Lydia S A1 - Badawi, Alaa A1 - Balakrishnan, Kalpana A1 - Banerjee, Amitava A1 - Basu, Sanjay A1 - Beardsley, Justin A1 - Bekele, Tolesa A1 - Bell, Michelle L A1 - Bernabe, Eduardo A1 - Beyene, Tariku Jibat A1 - Bhala, Neeraj A1 - Bhalla, Ashish A1 - Bhutta, Zulfiqar A A1 - Abdulhak, Aref Bin A1 - Binagwaho, Agnes A1 - Blore, Jed D A1 - Basara, Berrak Bora A1 - Bose, Dipan A1 - Brainin, Michael A1 - Breitborde, Nicholas A1 - Castañeda-Orjuela, Carlos A A1 - Catalá-López, Ferrán A1 - Chadha, Vineet K A1 - Chang, Jung-Chen A1 - Chiang, Peggy Pei-Chia A1 - Chuang, Ting-Wu A1 - Colomar, Mercedes A1 - Cooper, Leslie Trumbull A1 - Cooper, Cyrus A1 - Courville, Karen J A1 - Cowie, Benjamin C A1 - Criqui, Michael H A1 - Dandona, Rakhi A1 - Dayama, Anand A1 - De Leo, Diego A1 - Degenhardt, Louisa A1 - del Pozo-Cruz, Borja A1 - Deribe, Kebede A1 - Des Jarlais, Don C A1 - Dessalegn, Muluken A1 - Dharmaratne, Samath D A1 - Dilmen, Uğur A1 - Ding, Eric L A1 - Driscoll, Tim R A1 - Durrani, Adnan M A1 - Ellenbogen, Richard G A1 - Ermakov, Sergey Petrovich A1 - Esteghamati, Alireza A1 - Faraon, Emerito Jose A A1 - Farzadfar, Farshad A1 - Fereshtehnejad, Seyed-Mohammad A1 - Fijabi, Daniel Obadare A1 - Forouzanfar, Mohammad H A1 - Fra Paleo, Urbano A1 - Gaffikin, Lynne A1 - Gamkrelidze, Amiran A1 - Gankpé, Fortuné Gbètoho A1 - Geleijnse, Johanna M A1 - Gessner, Bradford D A1 - Gibney, Katherine B A1 - Ginawi, Ibrahim Abdelmageem Mohamed A1 - Glaser, Elizabeth L A1 - Gona, Philimon A1 - Goto, Atsushi A1 - Gouda, Hebe N A1 - Gugnani, Harish Chander A1 - Gupta, Rajeev A1 - Gupta, Rahul A1 - Hafezi-Nejad, Nima A1 - Hamadeh, Randah Ribhi A1 - Hammami, Mouhanad A1 - Hankey, Graeme J A1 - Harb, Hilda L A1 - Haro, Josep Maria A1 - Havmoeller, Rasmus A1 - Hay, Simon I A1 - Hedayati, Mohammad T A1 - Pi, Ileana B Heredia A1 - Hoek, Hans W A1 - Hornberger, John C A1 - Hosgood, H Dean A1 - Hotez, Peter J A1 - Hoy, Damian G A1 - Huang, John J A1 - Iburg, Kim M A1 - Idrisov, Bulat T A1 - Innos, Kaire A1 - Jacobsen, Kathryn H A1 - Jeemon, Panniyammakal A1 - Jensen, Paul N A1 - Jha, Vivekanand A1 - Jiang, Guohong A1 - Jonas, Jost B A1 - Juel, Knud A1 - Kan, Haidong A1 - Kankindi, Ida A1 - Karam, Nadim E A1 - Karch, André A1 - Karema, Corine Kakizi A1 - Kaul, Anil A1 - Kawakami, Norito A1 - Kazi, Dhruv S A1 - Kemp, Andrew H A1 - Kengne, Andre Pascal A1 - Keren, Andre A1 - Kereselidze, Maia A1 - Khader, Yousef Saleh A1 - Khalifa, Shams Eldin Ali Hassan A1 - Khan, Ejaz Ahmed A1 - Khang, Young-Ho A1 - Khonelidze, Irma A1 - Kinfu, Yohannes A1 - Kinge, Jonas M A1 - Knibbs, Luke A1 - Kokubo, Yoshihiro A1 - Kosen, S A1 - Defo, Barthelemy Kuate A1 - Kulkarni, Veena S A1 - Kulkarni, Chanda A1 - Kumar, Kaushalendra A1 - Kumar, Ravi B A1 - Kumar, G Anil A1 - Kwan, Gene F A1 - Lai, Taavi A1 - Balaji, Arjun Lakshmana A1 - Lam, Hilton A1 - Lan, Qing A1 - Lansingh, Van C A1 - Larson, Heidi J A1 - Larsson, Anders A1 - Lee, Jong-Tae A1 - Leigh, James A1 - Leinsalu, Mall A1 - Leung, Ricky A1 - Li, Yichong A1 - Li, Yongmei A1 - de Lima, Graça Maria Ferreira A1 - Lin, Hsien-Ho A1 - Lipshultz, Steven E A1 - Liu, Shiwei A1 - Liu, Yang A1 - Lloyd, Belinda K A1 - Lotufo, Paulo A A1 - Machado, Vasco Manuel Pedro A1 - Maclachlan, Jennifer H A1 - Magis-Rodriguez, Carlos A1 - Majdan, Marek A1 - Mapoma, Christopher Chabila A1 - Marcenes, Wagner A1 - Marzan, Melvin Barrientos A1 - Masci, Joseph R A1 - Mashal, Mohammad Taufiq A1 - Mason-Jones, Amanda J A1 - Mayosi, Bongani M A1 - Mazorodze, Tasara T A1 - Mckay, Abigail Cecilia A1 - Meaney, Peter A A1 - Mehndiratta, Man Mohan A1 - Mejia-Rodriguez, Fabiola A1 - Melaku, Yohannes Adama A1 - Memish, Ziad A A1 - Mendoza, Walter A1 - Miller, Ted R A1 - Mills, Edward J A1 - Mohammad, Karzan Abdulmuhsin A1 - Mokdad, Ali H A1 - Mola, Glen Liddell A1 - Monasta, Lorenzo A1 - Montico, Marcella A1 - Moore, Ami R A1 - Mori, Rintaro A1 - Moturi, Wilkister Nyaora A1 - Mukaigawara, Mitsuru A1 - Murthy, Kinnari S A1 - Naheed, Aliya A1 - Naidoo, Kovin S A1 - Naldi, Luigi A1 - Nangia, Vinay A1 - Narayan, K M Venkat A1 - Nash, Denis A1 - Nejjari, Chakib A1 - Nelson, Robert G A1 - Neupane, Sudan Prasad A1 - Newton, Charles R A1 - Ng, Marie A1 - Nisar, Muhammad Imran A1 - Nolte, Sandra A1 - Norheim, Ole F A1 - Nowaseb, Vincent A1 - Nyakarahuka, Luke A1 - Oh, In-Hwan A1 - Ohkubo, Takayoshi A1 - Olusanya, Bolajoko O A1 - Omer, Saad B A1 - Opio, John Nelson A1 - Orisakwe, Orish Ebere A1 - Pandian, Jeyaraj D A1 - Papachristou, Christina A1 - Caicedo, Angel J Paternina A1 - Patten, Scott B A1 - Paul, Vinod K A1 - Pavlin, Boris Igor A1 - Pearce, Neil A1 - Pereira, David M A1 - Pervaiz, Aslam A1 - Pesudovs, Konrad A1 - Petzold, Max A1 - Pourmalek, Farshad A1 - Qato, Dima A1 - Quezada, Amado D A1 - Quistberg, D Alex A1 - Rafay, Anwar A1 - Rahimi, Kazem A1 - Rahimi-Movaghar, Vafa A1 - ur Rahman, Sajjad A1 - Raju, Murugesan A1 - Rana, Saleem M A1 - Razavi, Homie A1 - Reilly, Robert Quentin A1 - Remuzzi, Giuseppe A1 - Richardus, Jan Hendrik A1 - Ronfani, Luca A1 - Roy, Nobhojit A1 - Sabin, Nsanzimana A1 - Saeedi, Mohammad Yahya A1 - Sahraian, Mohammad Ali A1 - Samonte, Genesis May J A1 - Sawhney, Monika A1 - Schneider, Ione J C A1 - Schwebel, David C A1 - Seedat, Soraya A1 - Sepanlou, Sadaf G A1 - Servan-Mori, Edson E A1 - Sheikhbahaei, Sara A1 - Shibuya, Kenji A1 - Shin, Hwashin Hyun A1 - Shiue, Ivy A1 - Shivakoti, Rupak A1 - Sigfusdottir, Inga Dora A1 - Silberberg, Donald H A1 - Silva, Andrea P A1 - Simard, Edgar P A1 - Singh, Jasvinder A A1 - Skirbekk, Vegard A1 - Sliwa, Karen A1 - Soneji, Samir A1 - Soshnikov, Sergey S A1 - Sreeramareddy, Chandrashekhar T A1 - Stathopoulou, Vasiliki Kalliopi A1 - Stroumpoulis, Konstantinos A1 - Swaminathan, Soumya A1 - Sykes, Bryan L A1 - Tabb, Karen M A1 - Talongwa, Roberto Tchio A1 - Tenkorang, Eric Yeboah A1 - Terkawi, Abdullah Sulieman A1 - Thomson, Alan J A1 - Thorne-Lyman, Andrew L A1 - Towbin, Jeffrey A A1 - Traebert, Jefferson A1 - Tran, Bach X A1 - Dimbuene, Zacharie Tsala A1 - Tsilimbaris, Miltiadis A1 - Uchendu, Uche S A1 - Ukwaja, Kingsley N A1 - Uzun, Selen Begüm A1 - Vallely, Andrew J A1 - Vasankari, Tommi J A1 - Venketasubramanian, N A1 - Violante, Francesco S A1 - Vlassov, Vasiliy Victorovich A1 - Vollset, Stein Emil A1 - Waller, Stephen A1 - Wallin, Mitchell T A1 - Wang, Linhong A1 - Wang, XiaoRong A1 - Wang, Yanping A1 - Weichenthal, Scott A1 - Weiderpass, Elisabete A1 - Weintraub, Robert G A1 - Westerman, Ronny A1 - White, Richard A A1 - Wilkinson, James D A1 - Williams, Thomas Neil A1 - Woldeyohannes, Solomon Meseret A1 - Wong, John Q A1 - Xu, Gelin A1 - Yang, Yang C A1 - Yano, Yuichiro A1 - Yentur, Gokalp Kadri A1 - Yip, Paul A1 - Yonemoto, Naohiro A1 - Yoon, Seok-Jun A1 - Younis, Mustafa A1 - Yu, Chuanhua A1 - Jin, Kim Yun A1 - El Sayed Zaki, Maysaa A1 - Zhao, Yong A1 - Zheng, Yingfeng A1 - Zhou, Maigeng A1 - Zhu, Jun A1 - Zou, Xiao Nong A1 - Lopez, Alan D A1 - Vos, Theo KW - Age Distribution KW - Epidemics KW - Female KW - Global Health KW - HIV Infections KW - Humans KW - Incidence KW - Malaria KW - Male KW - Mortality KW - Organizational Objectives KW - Sex Distribution KW - Tuberculosis AB -

BACKGROUND: The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occured since the Millennium Declaration.

METHODS: To estimate incidence and mortality for HIV, we used the UNAIDS Spectrum model appropriately modified based on a systematic review of available studies of mortality with and without antiretroviral therapy (ART). For concentrated epidemics, we calibrated Spectrum models to fit vital registration data corrected for misclassification of HIV deaths. In generalised epidemics, we minimised a loss function to select epidemic curves most consistent with prevalence data and demographic data for all-cause mortality. We analysed counterfactual scenarios for HIV to assess years of life saved through prevention of mother-to-child transmission (PMTCT) and ART. For tuberculosis, we analysed vital registration and verbal autopsy data to estimate mortality using cause of death ensemble modelling. We analysed data for corrected case-notifications, expert opinions on the case-detection rate, prevalence surveys, and estimated cause-specific mortality using Bayesian meta-regression to generate consistent trends in all parameters. We analysed malaria mortality and incidence using an updated cause of death database, a systematic analysis of verbal autopsy validation studies for malaria, and recent studies (2010-13) of incidence, drug resistance, and coverage of insecticide-treated bednets.

FINDINGS: Globally in 2013, there were 1·8 million new HIV infections (95% uncertainty interval 1·7 million to 2·1 million), 29·2 million prevalent HIV cases (28·1 to 31·7), and 1·3 million HIV deaths (1·3 to 1·5). At the peak of the epidemic in 2005, HIV caused 1·7 million deaths (1·6 million to 1·9 million). Concentrated epidemics in Latin America and eastern Europe are substantially smaller than previously estimated. Through interventions including PMTCT and ART, 19·1 million life-years (16·6 million to 21·5 million) have been saved, 70·3% (65·4 to 76·1) in developing countries. From 2000 to 2011, the ratio of development assistance for health for HIV to years of life saved through intervention was US$4498 in developing countries. Including in HIV-positive individuals, all-form tuberculosis incidence was 7·5 million (7·4 million to 7·7 million), prevalence was 11·9 million (11·6 million to 12·2 million), and number of deaths was 1·4 million (1·3 million to 1·5 million) in 2013. In the same year and in only individuals who were HIV-negative, all-form tuberculosis incidence was 7·1 million (6·9 million to 7·3 million), prevalence was 11·2 million (10·8 million to 11·6 million), and number of deaths was 1·3 million (1·2 million to 1·4 million). Annualised rates of change (ARC) for incidence, prevalence, and death became negative after 2000. Tuberculosis in HIV-negative individuals disproportionately occurs in men and boys (versus women and girls); 64·0% of cases (63·6 to 64·3) and 64·7% of deaths (60·8 to 70·3). Globally, malaria cases and deaths grew rapidly from 1990 reaching a peak of 232 million cases (143 million to 387 million) in 2003 and 1·2 million deaths (1·1 million to 1·4 million) in 2004. Since 2004, child deaths from malaria in sub-Saharan Africa have decreased by 31·5% (15·7 to 44·1). Outside of Africa, malaria mortality has been steadily decreasing since 1990.

INTERPRETATION: Our estimates of the number of people living with HIV are 18·7% smaller than UNAIDS's estimates in 2012. The number of people living with malaria is larger than estimated by WHO. The number of people living with HIV, tuberculosis, or malaria have all decreased since 2000. At the global level, upward trends for malaria and HIV deaths have been reversed and declines in tuberculosis deaths have accelerated. 101 countries (74 of which are developing) still have increasing HIV incidence. Substantial progress since the Millennium Declaration is an encouraging sign of the effect of global action.

FUNDING: Bill & Melinda Gates Foundation.

VL - 384 IS - 9947 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25059949?dopt=Abstract ER - TY - JOUR T1 - Global, regional, and national levels and causes of maternal mortality during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. JF - Lancet Y1 - 2014 A1 - Kassebaum, Nicholas J A1 - Bertozzi-Villa, Amelia A1 - Coggeshall, Megan S A1 - Shackelford, Katya A A1 - Steiner, Caitlyn A1 - Heuton, Kyle R A1 - Gonzalez-Medina, Diego A1 - Barber, Ryan A1 - Huynh, Chantal A1 - Dicker, Daniel A1 - Templin, Tara A1 - Wolock, Timothy M A1 - Ozgoren, Ayse Abbasoglu A1 - Abd-Allah, Foad A1 - Abera, Semaw Ferede A1 - Abubakar, Ibrahim A1 - Achoki, Tom A1 - Adelekan, Ademola A1 - Ademi, Zanfina A1 - Adou, Arsène Kouablan A1 - Adsuar, José C A1 - Agardh, Emilie E A1 - Akena, Dickens A1 - Alasfoor, Deena A1 - Alemu, Zewdie Aderaw A1 - Alfonso-Cristancho, Rafael A1 - Alhabib, Samia A1 - Ali, Raghib A1 - Al Kahbouri, Mazin J A1 - Alla, François A1 - Allen, Peter J A1 - AlMazroa, Mohammad A A1 - Alsharif, Ubai A1 - Alvarez, Elena A1 - Alvis-Guzmán, Nelson A1 - Amankwaa, Adansi A A1 - Amare, Azmeraw T A1 - Amini, Hassan A1 - Ammar, Walid A1 - Antonio, Carl A T A1 - Anwari, Palwasha A1 - Arnlöv, Johan A1 - Arsenijevic, Valentina S Arsic A1 - Artaman, Ali A1 - Asad, Majed Masoud A1 - Asghar, Rana J A1 - Assadi, Reza A1 - Atkins, Lydia S A1 - Badawi, Alaa A1 - Balakrishnan, Kalpana A1 - Basu, Arindam A1 - Basu, Sanjay A1 - Beardsley, Justin A1 - Bedi, Neeraj A1 - Bekele, Tolesa A1 - Bell, Michelle L A1 - Bernabe, Eduardo A1 - Beyene, Tariku J A1 - Bhutta, Zulfiqar A1 - Bin Abdulhak, Aref A1 - Blore, Jed D A1 - Basara, Berrak Bora A1 - Bose, Dipan A1 - Breitborde, Nicholas A1 - Cárdenas, Rosario A1 - Castañeda-Orjuela, Carlos A A1 - Castro, Ruben Estanislao A1 - Catalá-López, Ferrán A1 - Cavlin, Alanur A1 - Chang, Jung-Chen A1 - Che, Xuan A1 - Christophi, Costas A A1 - Chugh, Sumeet S A1 - Cirillo, Massimo A1 - Colquhoun, Samantha M A1 - Cooper, Leslie Trumbull A1 - Cooper, Cyrus A1 - da Costa Leite, Iuri A1 - Dandona, Lalit A1 - Dandona, Rakhi A1 - Davis, Adrian A1 - Dayama, Anand A1 - Degenhardt, Louisa A1 - De Leo, Diego A1 - del Pozo-Cruz, Borja A1 - Deribe, Kebede A1 - Dessalegn, Muluken A1 - deVeber, Gabrielle A A1 - Dharmaratne, Samath D A1 - Dilmen, Uğur A1 - Ding, Eric L A1 - Dorrington, Rob E A1 - Driscoll, Tim R A1 - Ermakov, Sergei Petrovich A1 - Esteghamati, Alireza A1 - Faraon, Emerito Jose A A1 - Farzadfar, Farshad A1 - Felicio, Manuela Mendonca A1 - Fereshtehnejad, Seyed-Mohammad A1 - de Lima, Graça Maria Ferreira A1 - Forouzanfar, Mohammad H A1 - França, Elisabeth B A1 - Gaffikin, Lynne A1 - Gambashidze, Ketevan A1 - Gankpé, Fortuné Gbètoho A1 - Garcia, Ana C A1 - Geleijnse, Johanna M A1 - Gibney, Katherine B A1 - Giroud, Maurice A1 - Glaser, Elizabeth L A1 - Goginashvili, Ketevan A1 - Gona, Philimon A1 - González-Castell, Dinorah A1 - Goto, Atsushi A1 - Gouda, Hebe N A1 - Gugnani, Harish Chander A1 - Gupta, Rahul A1 - Gupta, Rajeev A1 - Hafezi-Nejad, Nima A1 - Hamadeh, Randah Ribhi A1 - Hammami, Mouhanad A1 - Hankey, Graeme J A1 - Harb, Hilda L A1 - Havmoeller, Rasmus A1 - Hay, Simon I A1 - Pi, Ileana B Heredia A1 - Hoek, Hans W A1 - Hosgood, H Dean A1 - Hoy, Damian G A1 - Husseini, Abdullatif A1 - Idrisov, Bulat T A1 - Innos, Kaire A1 - Inoue, Manami A1 - Jacobsen, Kathryn H A1 - Jahangir, Eiman A1 - Jee, Sun Ha A1 - Jensen, Paul N A1 - Jha, Vivekanand A1 - Jiang, Guohong A1 - Jonas, Jost B A1 - Juel, Knud A1 - Kabagambe, Edmond Kato A1 - Kan, Haidong A1 - Karam, Nadim E A1 - Karch, André A1 - Karema, Corine Kakizi A1 - Kaul, Anil A1 - Kawakami, Norito A1 - Kazanjan, Konstantin A1 - Kazi, Dhruv S A1 - Kemp, Andrew H A1 - Kengne, Andre Pascal A1 - Kereselidze, Maia A1 - Khader, Yousef Saleh A1 - Khalifa, Shams Eldin Ali Hassan A1 - Khan, Ejaz Ahmed A1 - Khang, Young-Ho A1 - Knibbs, Luke A1 - Kokubo, Yoshihiro A1 - Kosen, Soewarta A1 - Defo, Barthelemy Kuate A1 - Kulkarni, Chanda A1 - Kulkarni, Veena S A1 - Kumar, G Anil A1 - Kumar, Kaushalendra A1 - Kumar, Ravi B A1 - Kwan, Gene A1 - Lai, Taavi A1 - Lalloo, Ratilal A1 - Lam, Hilton A1 - Lansingh, Van C A1 - Larsson, Anders A1 - Lee, Jong-Tae A1 - Leigh, James A1 - Leinsalu, Mall A1 - Leung, Ricky A1 - Li, Xiaohong A1 - Li, Yichong A1 - Li, Yongmei A1 - Liang, Juan A1 - Liang, Xiaofeng A1 - Lim, Stephen S A1 - Lin, Hsien-Ho A1 - Lipshultz, Steven E A1 - Liu, Shiwei A1 - Liu, Yang A1 - Lloyd, Belinda K A1 - London, Stephanie J A1 - Lotufo, Paulo A A1 - Ma, Jixiang A1 - Ma, Stefan A1 - Machado, Vasco Manuel Pedro A1 - Mainoo, Nana Kwaku A1 - Majdan, Marek A1 - Mapoma, Christopher Chabila A1 - Marcenes, Wagner A1 - Marzan, Melvin Barrientos A1 - Mason-Jones, Amanda J A1 - Mehndiratta, Man Mohan A1 - Mejia-Rodriguez, Fabiola A1 - Memish, Ziad A A1 - Mendoza, Walter A1 - Miller, Ted R A1 - Mills, Edward J A1 - Mokdad, Ali H A1 - Mola, Glen Liddell A1 - Monasta, Lorenzo A1 - de la Cruz Monis, Jonathan A1 - Hernandez, Julio Cesar Montañez A1 - Moore, Ami R A1 - Moradi-Lakeh, Maziar A1 - Mori, Rintaro A1 - Mueller, Ulrich O A1 - Mukaigawara, Mitsuru A1 - Naheed, Aliya A1 - Naidoo, Kovin S A1 - Nand, Devina A1 - Nangia, Vinay A1 - Nash, Denis A1 - Nejjari, Chakib A1 - Nelson, Robert G A1 - Neupane, Sudan Prasad A1 - Newton, Charles R A1 - Ng, Marie A1 - Nieuwenhuijsen, Mark J A1 - Nisar, Muhammad Imran A1 - Nolte, Sandra A1 - Norheim, Ole F A1 - Nyakarahuka, Luke A1 - Oh, In-Hwan A1 - Ohkubo, Takayoshi A1 - Olusanya, Bolajoko O A1 - Omer, Saad B A1 - Opio, John Nelson A1 - Orisakwe, Orish Ebere A1 - Pandian, Jeyaraj D A1 - Papachristou, Christina A1 - Park, Jae-Hyun A1 - Caicedo, Angel J Paternina A1 - Patten, Scott B A1 - Paul, Vinod K A1 - Pavlin, Boris Igor A1 - Pearce, Neil A1 - Pereira, David M A1 - Pesudovs, Konrad A1 - Petzold, Max A1 - Poenaru, Dan A1 - Polanczyk, Guilherme V A1 - Polinder, Suzanne A1 - Pope, Dan A1 - Pourmalek, Farshad A1 - Qato, Dima A1 - Quistberg, D Alex A1 - Rafay, Anwar A1 - Rahimi, Kazem A1 - Rahimi-Movaghar, Vafa A1 - ur Rahman, Sajjad A1 - Raju, Murugesan A1 - Rana, Saleem M A1 - Refaat, Amany A1 - Ronfani, Luca A1 - Roy, Nobhojit A1 - Pimienta, Tania Georgina Sánchez A1 - Sahraian, Mohammad Ali A1 - Salomon, Joshua A A1 - Sampson, Uchechukwu A1 - Santos, Itamar S A1 - Sawhney, Monika A1 - Sayinzoga, Felix A1 - Schneider, Ione J C A1 - Schumacher, Austin A1 - Schwebel, David C A1 - Seedat, Soraya A1 - Sepanlou, Sadaf G A1 - Servan-Mori, Edson E A1 - Shakh-Nazarova, Marina A1 - Sheikhbahaei, Sara A1 - Shibuya, Kenji A1 - Shin, Hwashin Hyun A1 - Shiue, Ivy A1 - Sigfusdottir, Inga Dora A1 - Silberberg, Donald H A1 - Silva, Andrea P A1 - Singh, Jasvinder A A1 - Skirbekk, Vegard A1 - Sliwa, Karen A1 - Soshnikov, Sergey S A1 - Sposato, Luciano A A1 - Sreeramareddy, Chandrashekhar T A1 - Stroumpoulis, Konstantinos A1 - Sturua, Lela A1 - Sykes, Bryan L A1 - Tabb, Karen M A1 - Talongwa, Roberto Tchio A1 - Tan, Feng A1 - Teixeira, Carolina Maria A1 - Tenkorang, Eric Yeboah A1 - Terkawi, Abdullah Sulieman A1 - Thorne-Lyman, Andrew L A1 - Tirschwell, David L A1 - Towbin, Jeffrey A A1 - Tran, Bach X A1 - Tsilimbaris, Miltiadis A1 - Uchendu, Uche S A1 - Ukwaja, Kingsley N A1 - Undurraga, Eduardo A A1 - Uzun, Selen Begüm A1 - Vallely, Andrew J A1 - van Gool, Coen H A1 - Vasankari, Tommi J A1 - Vavilala, Monica S A1 - Venketasubramanian, N A1 - Villalpando, Salvador A1 - Violante, Francesco S A1 - Vlassov, Vasiliy Victorovich A1 - Vos, Theo A1 - Waller, Stephen A1 - Wang, Haidong A1 - Wang, Linhong A1 - Wang, XiaoRong A1 - Wang, Yanping A1 - Weichenthal, Scott A1 - Weiderpass, Elisabete A1 - Weintraub, Robert G A1 - Westerman, Ronny A1 - Wilkinson, James D A1 - Woldeyohannes, Solomon Meseret A1 - Wong, John Q A1 - Wordofa, Muluemebet Abera A1 - Xu, Gelin A1 - Yang, Yang C A1 - Yano, Yuichiro A1 - Yentur, Gokalp Kadri A1 - Yip, Paul A1 - Yonemoto, Naohiro A1 - Yoon, Seok-Jun A1 - Younis, Mustafa Z A1 - Yu, Chuanhua A1 - Jin, Kim Yun A1 - El Sayed Zaki, Maysaa A1 - Zhao, Yong A1 - Zheng, Yingfeng A1 - Zhou, Maigeng A1 - Zhu, Jun A1 - Zou, Xiao Nong A1 - Lopez, Alan D A1 - Naghavi, Mohsen A1 - Murray, Christopher J L A1 - Lozano, Rafael KW - Age Distribution KW - Cause of Death KW - Female KW - Global Health KW - HIV Infections KW - Humans KW - Maternal Mortality KW - Models, Statistical KW - Organizational Objectives KW - Pregnancy KW - Pregnancy Complications, Infectious KW - Risk Factors KW - Socioeconomic Factors KW - Time Factors AB -

BACKGROUND: The fifth Millennium Development Goal (MDG 5) established the goal of a 75% reduction in the maternal mortality ratio (MMR; number of maternal deaths per 100,000 livebirths) between 1990 and 2015. We aimed to measure levels and track trends in maternal mortality, the key causes contributing to maternal death, and timing of maternal death with respect to delivery.

METHODS: We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to analyse a database of data for 7065 site-years and estimate the number of maternal deaths from all causes in 188 countries between 1990 and 2013. We estimated the number of pregnancy-related deaths caused by HIV on the basis of a systematic review of the relative risk of dying during pregnancy for HIV-positive women compared with HIV-negative women. We also estimated the fraction of these deaths aggravated by pregnancy on the basis of a systematic review. To estimate the numbers of maternal deaths due to nine different causes, we identified 61 sources from a systematic review and 943 site-years of vital registration data. We also did a systematic review of reports about the timing of maternal death, identifying 142 sources to use in our analysis. We developed estimates for each country for 1990-2013 using Bayesian meta-regression. We estimated 95% uncertainty intervals (UIs) for all values.

FINDINGS: 292,982 (95% UI 261,017-327,792) maternal deaths occurred in 2013, compared with 376,034 (343,483-407,574) in 1990. The global annual rate of change in the MMR was -0·3% (-1·1 to 0·6) from 1990 to 2003, and -2·7% (-3·9 to -1·5) from 2003 to 2013, with evidence of continued acceleration. MMRs reduced consistently in south, east, and southeast Asia between 1990 and 2013, but maternal deaths increased in much of sub-Saharan Africa during the 1990s. 2070 (1290-2866) maternal deaths were related to HIV in 2013, 0·4% (0·2-0·6) of the global total. MMR was highest in the oldest age groups in both 1990 and 2013. In 2013, most deaths occurred intrapartum or postpartum. Causes varied by region and between 1990 and 2013. We recorded substantial variation in the MMR by country in 2013, from 956·8 (685·1-1262·8) in South Sudan to 2·4 (1·6-3·6) in Iceland.

INTERPRETATION: Global rates of change suggest that only 16 countries will achieve the MDG 5 target by 2015. Accelerated reductions since the Millennium Declaration in 2000 coincide with increased development assistance for maternal, newborn, and child health. Setting of targets and associated interventions for after 2015 will need careful consideration of regions that are making slow progress, such as west and central Africa.

FUNDING: Bill & Melinda Gates Foundation.

VL - 384 IS - 9947 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24797575?dopt=Abstract ER - TY - JOUR T1 - Global, regional, and national levels of neonatal, infant, and under-5 mortality during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. JF - Lancet Y1 - 2014 A1 - Wang, Haidong A1 - Liddell, Chelsea A A1 - Coates, Matthew M A1 - Mooney, Meghan D A1 - Levitz, Carly E A1 - Schumacher, Austin E A1 - Apfel, Henry A1 - Iannarone, Marissa A1 - Phillips, Bryan A1 - Lofgren, Katherine T A1 - Sandar, Logan A1 - Dorrington, Rob E A1 - Rakovac, Ivo A1 - Jacobs, Troy A A1 - Liang, Xiaofeng A1 - Zhou, Maigeng A1 - Zhu, Jun A1 - Yang, Gonghuan A1 - Wang, Yanping A1 - Liu, Shiwei A1 - Li, Yichong A1 - Ozgoren, Ayse Abbasoglu A1 - Abera, Semaw Ferede A1 - Abubakar, Ibrahim A1 - Achoki, Tom A1 - Adelekan, Ademola A1 - Ademi, Zanfina A1 - Alemu, Zewdie Aderaw A1 - Allen, Peter J A1 - AlMazroa, Mohammad AbdulAziz A1 - Alvarez, Elena A1 - Amankwaa, Adansi A A1 - Amare, Azmeraw T A1 - Ammar, Walid A1 - Anwari, Palwasha A1 - Cunningham, Solveig Argeseanu A1 - Asad, Majed Masoud A1 - Assadi, Reza A1 - Banerjee, Amitava A1 - Basu, Sanjay A1 - Bedi, Neeraj A1 - Bekele, Tolesa A1 - Bell, Michelle L A1 - Bhutta, Zulfiqar A1 - Blore, Jed D A1 - Basara, Berrak Bora A1 - Boufous, Soufiane A1 - Breitborde, Nicholas A1 - Bruce, Nigel G A1 - Bui, Linh Ngoc A1 - Carapetis, Jonathan R A1 - Cárdenas, Rosario A1 - Carpenter, David O A1 - Caso, Valeria A1 - Castro, Ruben Estanislao A1 - Catalá-López, Ferrán A1 - Cavlin, Alanur A1 - Che, Xuan A1 - Chiang, Peggy Pei-Chia A1 - Chowdhury, Rajiv A1 - Christophi, Costas A A1 - Chuang, Ting-Wu A1 - Cirillo, Massimo A1 - da Costa Leite, Iuri A1 - Courville, Karen J A1 - Dandona, Lalit A1 - Dandona, Rakhi A1 - Davis, Adrian A1 - Dayama, Anand A1 - Deribe, Kebede A1 - Dharmaratne, Samath D A1 - Dherani, Mukesh K A1 - Dilmen, Uğur A1 - Ding, Eric L A1 - Edmond, Karen M A1 - Ermakov, Sergei Petrovich A1 - Farzadfar, Farshad A1 - Fereshtehnejad, Seyed-Mohammad A1 - Fijabi, Daniel Obadare A1 - Foigt, Nataliya A1 - Forouzanfar, Mohammad H A1 - Garcia, Ana C A1 - Geleijnse, Johanna M A1 - Gessner, Bradford D A1 - Goginashvili, Ketevan A1 - Gona, Philimon A1 - Goto, Atsushi A1 - Gouda, Hebe N A1 - Green, Mark A A1 - Greenwell, Karen Fern A1 - Gugnani, Harish Chander A1 - Gupta, Rahul A1 - Hamadeh, Randah Ribhi A1 - Hammami, Mouhanad A1 - Harb, Hilda L A1 - Hay, Simon A1 - Hedayati, Mohammad T A1 - Hosgood, H Dean A1 - Hoy, Damian G A1 - Idrisov, Bulat T A1 - Islami, Farhad A1 - Ismayilova, Samaya A1 - Jha, Vivekanand A1 - Jiang, Guohong A1 - Jonas, Jost B A1 - Juel, Knud A1 - Kabagambe, Edmond Kato A1 - Kazi, Dhruv S A1 - Kengne, Andre Pascal A1 - Kereselidze, Maia A1 - Khader, Yousef Saleh A1 - Khalifa, Shams Eldin Ali Hassan A1 - Khang, Young-Ho A1 - Kim, Daniel A1 - Kinfu, Yohannes A1 - Kinge, Jonas M A1 - Kokubo, Yoshihiro A1 - Kosen, Soewarta A1 - Defo, Barthelemy Kuate A1 - Kumar, G Anil A1 - Kumar, Kaushalendra A1 - Kumar, Ravi B A1 - Lai, Taavi A1 - Lan, Qing A1 - Larsson, Anders A1 - Lee, Jong-Tae A1 - Leinsalu, Mall A1 - Lim, Stephen S A1 - Lipshultz, Steven E A1 - Logroscino, Giancarlo A1 - Lotufo, Paulo A A1 - Lunevicius, Raimundas A1 - Lyons, Ronan Anthony A1 - Ma, Stefan A1 - Mahdi, Abbas Ali A1 - Marzan, Melvin Barrientos A1 - Mashal, Mohammad Taufiq A1 - Mazorodze, Tasara T A1 - McGrath, John J A1 - Memish, Ziad A A1 - Mendoza, Walter A1 - Mensah, George A A1 - Meretoja, Atte A1 - Miller, Ted R A1 - Mills, Edward J A1 - Mohammad, Karzan Abdulmuhsin A1 - Mokdad, Ali H A1 - Monasta, Lorenzo A1 - Montico, Marcella A1 - Moore, Ami R A1 - Moschandreas, Joanna A1 - Msemburi, William T A1 - Mueller, Ulrich O A1 - Muszynska, Magdalena M A1 - Naghavi, Mohsen A1 - Naidoo, Kovin S A1 - Narayan, K M Venkat A1 - Nejjari, Chakib A1 - Ng, Marie A1 - de Dieu Ngirabega, Jean A1 - Nieuwenhuijsen, Mark J A1 - Nyakarahuka, Luke A1 - Ohkubo, Takayoshi A1 - Omer, Saad B A1 - Caicedo, Angel J Paternina A1 - Pillay-van Wyk, Victoria A1 - Pope, Dan A1 - Pourmalek, Farshad A1 - Prabhakaran, Dorairaj A1 - Rahman, Sajjad U R A1 - Rana, Saleem M A1 - Reilly, Robert Quentin A1 - Rojas-Rueda, David A1 - Ronfani, Luca A1 - Rushton, Lesley A1 - Saeedi, Mohammad Yahya A1 - Salomon, Joshua A A1 - Sampson, Uchechukwu A1 - Santos, Itamar S A1 - Sawhney, Monika A1 - Schmidt, Jürgen C A1 - Shakh-Nazarova, Marina A1 - She, Jun A1 - Sheikhbahaei, Sara A1 - Shibuya, Kenji A1 - Shin, Hwashin Hyun A1 - Shishani, Kawkab A1 - Shiue, Ivy A1 - Sigfusdottir, Inga Dora A1 - Singh, Jasvinder A A1 - Skirbekk, Vegard A1 - Sliwa, Karen A1 - Soshnikov, Sergey S A1 - Sposato, Luciano A A1 - Stathopoulou, Vasiliki Kalliopi A1 - Stroumpoulis, Konstantinos A1 - Tabb, Karen M A1 - Talongwa, Roberto Tchio A1 - Teixeira, Carolina Maria A1 - Terkawi, Abdullah Sulieman A1 - Thomson, Alan J A1 - Thorne-Lyman, Andrew L A1 - Toyoshima, Hideaki A1 - Dimbuene, Zacharie Tsala A1 - Uwaliraye, Parfait A1 - Uzun, Selen Begüm A1 - Vasankari, Tommi J A1 - Vasconcelos, Ana Maria Nogales A1 - Vlassov, Vasiliy Victorovich A1 - Vollset, Stein Emil A1 - Waller, Stephen A1 - Wan, Xia A1 - Weichenthal, Scott A1 - Weiderpass, Elisabete A1 - Weintraub, Robert G A1 - Westerman, Ronny A1 - Wilkinson, James D A1 - Williams, Hywel C A1 - Yang, Yang C A1 - Yentur, Gokalp Kadri A1 - Yip, Paul A1 - Yonemoto, Naohiro A1 - Younis, Mustafa A1 - Yu, Chuanhua A1 - Jin, Kim Yun A1 - El Sayed Zaki, Maysaa A1 - Zhu, Shankuan A1 - Vos, Theo A1 - Lopez, Alan D A1 - Murray, Christopher J L KW - Child Mortality KW - Child, Preschool KW - Global Health KW - Humans KW - Infant KW - Infant Mortality KW - Infant, Newborn KW - Organizational Objectives KW - Risk Factors KW - Socioeconomic Factors AB -

BACKGROUND: Remarkable financial and political efforts have been focused on the reduction of child mortality during the past few decades. Timely measurements of levels and trends in under-5 mortality are important to assess progress towards the Millennium Development Goal 4 (MDG 4) target of reduction of child mortality by two thirds from 1990 to 2015, and to identify models of success.

METHODS: We generated updated estimates of child mortality in early neonatal (age 0-6 days), late neonatal (7-28 days), postneonatal (29-364 days), childhood (1-4 years), and under-5 (0-4 years) age groups for 188 countries from 1970 to 2013, with more than 29,000 survey, census, vital registration, and sample registration datapoints. We used Gaussian process regression with adjustments for bias and non-sampling error to synthesise the data for under-5 mortality for each country, and a separate model to estimate mortality for more detailed age groups. We used explanatory mixed effects regression models to assess the association between under-5 mortality and income per person, maternal education, HIV child death rates, secular shifts, and other factors. To quantify the contribution of these different factors and birth numbers to the change in numbers of deaths in under-5 age groups from 1990 to 2013, we used Shapley decomposition. We used estimated rates of change between 2000 and 2013 to construct under-5 mortality rate scenarios out to 2030.

FINDINGS: We estimated that 6·3 million (95% UI 6·0-6·6) children under-5 died in 2013, a 64% reduction from 17·6 million (17·1-18·1) in 1970. In 2013, child mortality rates ranged from 152·5 per 1000 livebirths (130·6-177·4) in Guinea-Bissau to 2·3 (1·8-2·9) per 1000 in Singapore. The annualised rates of change from 1990 to 2013 ranged from -6·8% to 0·1%. 99 of 188 countries, including 43 of 48 countries in sub-Saharan Africa, had faster decreases in child mortality during 2000-13 than during 1990-2000. In 2013, neonatal deaths accounted for 41·6% of under-5 deaths compared with 37·4% in 1990. Compared with 1990, in 2013, rising numbers of births, especially in sub-Saharan Africa, led to 1·4 million more child deaths, and rising income per person and maternal education led to 0·9 million and 2·2 million fewer deaths, respectively. Changes in secular trends led to 4·2 million fewer deaths. Unexplained factors accounted for only -1% of the change in child deaths. In 30 developing countries, decreases since 2000 have been faster than predicted attributable to income, education, and secular shift alone.

INTERPRETATION: Only 27 developing countries are expected to achieve MDG 4. Decreases since 2000 in under-5 mortality rates are accelerating in many developing countries, especially in sub-Saharan Africa. The Millennium Declaration and increased development assistance for health might have been a factor in faster decreases in some developing countries. Without further accelerated progress, many countries in west and central Africa will still have high levels of under-5 mortality in 2030.

FUNDING: Bill & Melinda Gates Foundation, US Agency for International Development.

VL - 384 IS - 9947 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24797572?dopt=Abstract ER - TY - JOUR T1 - HLA-G 14 bp deletion/insertion polymorphism and mother-to-child transmission of HIV. JF - Tissue Antigens Y1 - 2014 A1 - Segat, L A1 - Zupin, L A1 - Kim, H-Y A1 - Catamo, E A1 - Thea, D M A1 - Kankasa, C A1 - Aldrovandi, G M A1 - Kuhn, L A1 - Crovella, S KW - Adult KW - Alleles KW - Base Pairing KW - Child KW - Genotype KW - HIV Infections KW - HLA-G Antigens KW - Humans KW - INDEL Mutation KW - Infant KW - Infectious Disease Transmission, Vertical KW - Mothers KW - Polymorphism, Genetic KW - Young Adult AB -

The human leukocyte antigen HLA-G, highly expressed at the maternal-fetal interface, has a pivotal role in mediating immune tolerance. In this study we investigated the influence of HLA-G 14 bp insertion polymorphism in human immunodeficiency virus (HIV)-1 mother-to-child HIV-1 transmission. The 14 bp insertion polymorphism was analyzed among 99 HIV-1 positive mothers and 329 infants born to HIV-positive mothers in Zambia, among whom vertical transmission status and timing had been determined. HLA-G 14 bp insertion polymorphism was detected using a custom TaqMan single nucleotide polymorphisms (SNPs) genotyping assay. Logistic regression was conducted to examine the associations between HLA-G alleles and the risk of HIV transmission. The 14 bp insertion allele was more frequent in HIV exposed-uninfected (EU) infants than in infected infants, and was associated with reduced risk of both in utero (IU) and intrapartum (IP) HIV transmission, after adjusting for maternal cluster of differentiation 4 (CD4) cell count and plasma viral load. Maternal HLA-G 14 bp insertion genotype and HLA-G concordance between mother and child were not associated with the risk of perinatal HIV transmission. The presence of the 14 bp insertion associates with protection toward IU and IP HIV infection in children from Zambia, suggesting that HLA-G could be involved in the vertical transmission of HIV.

VL - 83 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24571474?dopt=Abstract ER - TY - JOUR T1 - Influence of HLA-G polymorphisms in human immunodeficiency virus infection and hepatitis C virus co-infection in Brazilian and Italian individuals. JF - Infect Genet Evol Y1 - 2014 A1 - da Silva, G K A1 - Vianna, Priscila A1 - Veit, Tiago Degani A1 - Crovella, Sergio A1 - Catamo, Eulalia A1 - Cordero, Elvira Alicia Aparicio A1 - Mattevi, Vanessa Suñé A1 - Lazzaretti, Rosmeri Kuhmmer A1 - Sprinz, Eduardo A1 - Kuhmmer, Regina A1 - Chies, José Artur Bogo KW - 3' Untranslated Regions KW - Adolescent KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Brazil KW - Coinfection KW - Gene Frequency KW - Genetic Variation KW - Haplotypes KW - Hepatitis C KW - HIV Infections KW - HLA-G Antigens KW - Humans KW - Italy KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Young Adult AB -

OBJECTIVE: This study aimed to investigate the role of Human Leukocyte Antigen (HLA)-G in the susceptibility to HIV-1 infection through the analysis of the HLA-G 3' untranslated region (UTR) polymorphisms 14 bp insertion/deletion (rs66554220) and +3142C>G (rs1063320).

DESIGN: We analyzed 582 HIV-1 infected patients and 626 uninfected individuals from Brazil and Italy in a case-control study.

METHODS: HLA-G polymorphisms were genotyped using PCR, PCR-RFLP assays or direct sequencing. All analyses were stratified by ethnicity. Genotypic, allelic and diplotypic frequencies were compared between HIV-1 infected subjects and controls using Chi-square or Fischer exact tests. Also, haplotypic frequencies were estimated using MLocus software.

RESULTS: African-derived HIV-infected individuals presented a higher frequency of the 14 bp insertion allele as compared to non-infected individuals (0.468 versus 0.373, respectively; p(Bonf) = 0.010). A higher frequency of the 14 bp insertion +3142G (insG) haplotype (0.456 versus 0.346, p<0.001) and the insG/insG diplotype (OR=1.88, 95%CI = 1.08-3.23, p=0.021) was observed among African-derived patients as compared to uninfected controls. Also, we observed a higher frequency of the ins/ins genotype among African-derived HIV patients co-infected with HCV (OR=2.78, 95%CI = 1.20-6.49, p = 0.008).

CONCLUSIONS: Our data point out to an increased frequency of alleles and genotypes associated with low HLA-G expression among African-derived patients, suggesting a potential role for HLA-G in the susceptibility to HIV-1 infection and HCV co-infection in those individuals.

VL - 21 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24389119?dopt=Abstract ER - TY - JOUR T1 - Mevalonate kinase deficiency and IBD: shared genetic background. JF - Gut Y1 - 2014 A1 - Bianco, Anna Monica A1 - Girardelli, Martina A1 - Vozzi, Diego A1 - Crovella, Sergio A1 - Kleiner, Giulio A1 - Marcuzzi, Annalisa KW - Genetic Predisposition to Disease KW - Humans KW - Inflammatory Bowel Diseases VL - 63 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24531851?dopt=Abstract ER - TY - JOUR T1 - Midline 1 directs lytic granule exocytosis and cytotoxicity of mouse killer T cells. JF - Eur J Immunol Y1 - 2014 A1 - Boding, Lasse A1 - Hansen, Ann K A1 - Meroni, Germana A1 - Johansen, Bo B A1 - Braunstein, Thomas H A1 - Bonefeld, Charlotte M A1 - Kongsbak, Martin A1 - Jensen, Benjamin A H A1 - Woetmann, Anders A1 - Thomsen, Allan R A1 - Odum, Niels A1 - von Essen, Marina R A1 - Geisler, Carsten KW - Animals KW - Blotting, Western KW - Cytotoxicity, Immunologic KW - Exocytosis KW - Flow Cytometry KW - Mice KW - Mice, Knockout KW - Mice, Transgenic KW - Proteins KW - Reverse Transcriptase Polymerase Chain Reaction KW - Secretory Vesicles KW - T-Lymphocytes, Cytotoxic AB -

Midline 1 (MID1) is a microtubule-associated ubiquitin ligase that regulates protein phosphatase 2A activity. Loss-of-function mutations in MID1 lead to the X-linked Opitz G/BBB syndrome characterized by defective midline development during embryogenesis. Here, we show that MID1 is strongly upregulated in murine cytotoxic lymphocytes (CTLs), and that it controls TCR signaling, centrosome trafficking, and exocytosis of lytic granules. In accordance, we find that the killing capacity of MID1(-/-) CTLs is impaired. Transfection of MID1 into MID1(-/-) CTLs completely rescued lytic granule exocytosis, and vice versa, knockdown of MID1 inhibited exocytosis of lytic granules in WT CTLs, cementing a central role for MID1 in the regulation of granule exocytosis. Thus, MID1 orchestrates multiple events in CTL responses, adding a novel level of regulation to CTL activation and cytotoxicity.

VL - 44 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25043946?dopt=Abstract ER - TY - JOUR T1 - MYH9-related disease: a novel prognostic model to predict the clinical evolution of the disease based on genotype-phenotype correlations. JF - Hum Mutat Y1 - 2014 A1 - Pecci, Alessandro A1 - Klersy, Catherine A1 - Gresele, Paolo A1 - Lee, Kieran J D A1 - De Rocco, Daniela A1 - Bozzi, Valeria A1 - Russo, Giovanna A1 - Heller, Paula G A1 - Loffredo, Giuseppe A1 - Ballmaier, Matthias A1 - Fabris, Fabrizio A1 - Beggiato, Eloise A1 - Kahr, Walter H A A1 - Pujol-Moix, Núria A1 - Platokouki, Helen A1 - Van Geet, Christel A1 - Noris, Patrizia A1 - Yerram, Preethi A1 - Hermans, Cedric A1 - Gerber, Bernhard A1 - Economou, Marina A1 - De Groot, Marco A1 - Zieger, Barbara A1 - De Candia, Erica A1 - Fraticelli, Vincenzo A1 - Kersseboom, Rogier A1 - Piccoli, Giorgina B A1 - Zimmermann, Stefanie A1 - Fierro, Tiziana A1 - Glembotsky, Ana C A1 - Vianello, Fabrizio A1 - Zaninetti, Carlo A1 - Nicchia, Elena A1 - Güthner, Christiane A1 - Baronci, Carlo A1 - Seri, Marco A1 - Knight, Peter J A1 - Balduini, Carlo L A1 - Savoia, Anna KW - Adult KW - Age of Onset KW - Amino Acid Substitution KW - Cataract KW - Female KW - Genetic Association Studies KW - Genotype KW - Hearing Loss, Sensorineural KW - Humans KW - Italy KW - Linear Models KW - Male KW - Molecular Motor Proteins KW - Mutation KW - Myosin Heavy Chains KW - Phenotype KW - Risk Factors KW - Thrombocytopenia AB -

MYH9-related disease (MYH9-RD) is a rare autosomal-dominant disorder caused by mutations in the gene for nonmuscle myosin heavy chain IIA (NMMHC-IIA). MYH9-RD is characterized by a considerable variability in clinical evolution: patients present at birth with only thrombocytopenia, but some of them subsequently develop sensorineural deafness, cataract, and/or nephropathy often leading to end-stage renal disease (ESRD). We searched for genotype-phenotype correlations in the largest series of consecutive MYH9-RD patients collected so far (255 cases from 121 families). Association of genotypes with noncongenital features was assessed by a generalized linear regression model. The analysis defined disease evolution associated to seven different MYH9 genotypes that are responsible for 85% of MYH9-RD cases. Mutations hitting residue R702 demonstrated a complete penetrance for early-onset ESRD and deafness. The p.D1424H substitution associated with high risk of developing all the noncongenital manifestations of disease. Mutations hitting a distinct hydrophobic seam in the NMMHC-IIA head domain or substitutions at R1165 associated with high risk of deafness but low risk of nephropathy or cataract. Patients with p.E1841K, p.D1424N, and C-terminal deletions had low risk of noncongenital defects. These findings are essential to patients' clinical management and genetic counseling and are discussed in view of molecular pathogenesis of MYH9-RD.

VL - 35 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24186861?dopt=Abstract ER - TY - JOUR T1 - NLRP3 polymorphism is associated with protection against human T-lymphotropic virus 1 infection. JF - Mem Inst Oswaldo Cruz Y1 - 2014 A1 - Kamada, Anselmo Jiro A1 - Pontillo, Alessandra A1 - Guimarães, Rafael Lima A1 - Loureiro, Paula A1 - Crovella, Sergio A1 - Brandão, Lucas André Cavalcanti KW - Adult KW - Brazil KW - Carrier Proteins KW - Female KW - Genetic Predisposition to Disease KW - HTLV-I Infections KW - Human T-lymphotropic virus 1 KW - Humans KW - Inflammasomes KW - Interleukin-1 KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Protective Factors AB -

Inter-individual heterogeneity in the response to human T-lymphotropic virus 1 (HTLV-1) infection has been partially attributed to host genetic background. The antiviral activity of the inflammasome cytoplasmic complex recognises viral molecular patterns and regulates immune responses via the activation of interleukin (IL)-1 family (IL-1, IL-18 and IL-33) members. The association between polymorphisms in the inflammasome receptors NLRP1 and NLRP3 and HTLV-1 infection was evaluated in a northeastern Brazilian population (84 HTLV-1 carriers and 155 healthy controls). NLRP3 rs10754558 G/G was associated with protection against HTLV-1 infection (p = 0.012; odds ratio = 0.37). rs10754558 affects NLRP3 mRNA stability; therefore, our results suggest that higher NLRP3 expression may augment first-line defences, leading to the effective protection against HTLV-1 infection.

VL - 109 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25411003?dopt=Abstract ER - TY - JOUR T1 - Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. JF - Nature Y1 - 2014 A1 - Perry, John R B A1 - Day, Felix A1 - Elks, Cathy E A1 - Sulem, Patrick A1 - Thompson, Deborah J A1 - Ferreira, Teresa A1 - He, Chunyan A1 - Chasman, Daniel I A1 - Esko, Tõnu A1 - Thorleifsson, Gudmar A1 - Albrecht, Eva A1 - Ang, Wei Q A1 - Corre, Tanguy A1 - Cousminer, Diana L A1 - Feenstra, Bjarke A1 - Franceschini, Nora A1 - Ganna, Andrea A1 - Johnson, Andrew D A1 - Kjellqvist, Sanela A1 - Lunetta, Kathryn L A1 - McMahon, George A1 - Nolte, Ilja M A1 - Paternoster, Lavinia A1 - Porcu, Eleonora A1 - Smith, Albert V A1 - Stolk, Lisette A1 - Teumer, Alexander A1 - Tšernikova, Natalia A1 - Tikkanen, Emmi A1 - Ulivi, Sheila A1 - Wagner, Erin K A1 - Amin, Najaf A1 - Bierut, Laura J A1 - Byrne, Enda M A1 - Hottenga, Jouke-Jan A1 - Koller, Daniel L A1 - Mangino, Massimo A1 - Pers, Tune H A1 - Yerges-Armstrong, Laura M A1 - Hua Zhao, Jing A1 - Andrulis, Irene L A1 - Anton-Culver, Hoda A1 - Atsma, Femke A1 - Bandinelli, Stefania A1 - Beckmann, Matthias W A1 - Benitez, Javier A1 - Blomqvist, Carl A1 - Bojesen, Stig E A1 - Bolla, Manjeet K A1 - Bonanni, Bernardo A1 - Brauch, Hiltrud A1 - Brenner, Hermann A1 - Buring, Julie E A1 - Chang-Claude, Jenny A1 - Chanock, Stephen A1 - Chen, Jinhui A1 - Chenevix-Trench, Georgia A1 - Collée, J Margriet A1 - Couch, Fergus J A1 - Couper, David A1 - Coviello, Andrea D A1 - Cox, Angela A1 - Czene, Kamila A1 - d'Adamo, Adamo Pio A1 - Davey Smith, George A1 - De Vivo, Immaculata A1 - Demerath, Ellen W A1 - Dennis, Joe A1 - Devilee, Peter A1 - Dieffenbach, Aida K A1 - Dunning, Alison M A1 - Eiriksdottir, Gudny A1 - Eriksson, Johan G A1 - Fasching, Peter A A1 - Ferrucci, Luigi A1 - Flesch-Janys, Dieter A1 - Flyger, Henrik A1 - Foroud, Tatiana A1 - Franke, Lude A1 - Garcia, Melissa E A1 - García-Closas, Montserrat A1 - Geller, Frank A1 - de Geus, Eco E J A1 - Giles, Graham G A1 - Gudbjartsson, Daniel F A1 - Gudnason, Vilmundur A1 - Guenel, Pascal A1 - Guo, Suiqun A1 - Hall, Per A1 - Hamann, Ute A1 - Haring, Robin A1 - Hartman, Catharina A A1 - Heath, Andrew C A1 - Hofman, Albert A1 - Hooning, Maartje J A1 - Hopper, John L A1 - Hu, Frank B A1 - Hunter, David J A1 - Karasik, David A1 - Kiel, Douglas P A1 - Knight, Julia A A1 - Kosma, Veli-Matti A1 - Kutalik, Zoltán A1 - Lai, Sandra A1 - Lambrechts, Diether A1 - Lindblom, Annika A1 - Mägi, Reedik A1 - Magnusson, Patrik K A1 - Mannermaa, Arto A1 - Martin, Nicholas G A1 - Masson, Gisli A1 - McArdle, Patrick F A1 - McArdle, Wendy L A1 - Melbye, Mads A1 - Michailidou, Kyriaki A1 - Mihailov, Evelin A1 - Milani, Lili A1 - Milne, Roger L A1 - Nevanlinna, Heli A1 - Neven, Patrick A1 - Nohr, Ellen A A1 - Oldehinkel, Albertine J A1 - Oostra, Ben A A1 - Palotie, Aarno A1 - Peacock, Munro A1 - Pedersen, Nancy L A1 - Peterlongo, Paolo A1 - Peto, Julian A1 - Pharoah, Paul D P A1 - Postma, Dirkje S A1 - Pouta, Anneli A1 - Pylkäs, Katri A1 - Radice, Paolo A1 - Ring, Susan A1 - Rivadeneira, Fernando A1 - Robino, Antonietta A1 - Rose, Lynda M A1 - Rudolph, Anja A1 - Salomaa, Veikko A1 - Sanna, Serena A1 - Schlessinger, David A1 - Schmidt, Marjanka K A1 - Southey, Mellissa C A1 - Sovio, Ulla A1 - Stampfer, Meir J A1 - Stöckl, Doris A1 - Storniolo, Anna M A1 - Timpson, Nicholas J A1 - Tyrer, Jonathan A1 - Visser, Jenny A A1 - Vollenweider, Peter A1 - Völzke, Henry A1 - Waeber, Gerard A1 - Waldenberger, Melanie A1 - Wallaschofski, Henri A1 - Wang, Qin A1 - Willemsen, Gonneke A1 - Winqvist, Robert A1 - Wolffenbuttel, Bruce H R A1 - Wright, Margaret J A1 - Boomsma, Dorret I A1 - Econs, Michael J A1 - Khaw, Kay-Tee A1 - Loos, Ruth J F A1 - McCarthy, Mark I A1 - Montgomery, Grant W A1 - Rice, John P A1 - Streeten, Elizabeth A A1 - Thorsteinsdottir, Unnur A1 - van Duijn, Cornelia M A1 - Alizadeh, Behrooz Z A1 - Bergmann, Sven A1 - Boerwinkle, Eric A1 - Boyd, Heather A A1 - Crisponi, Laura A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Harris, Tamara B A1 - Ingelsson, Erik A1 - Järvelin, Marjo-Riitta A1 - Kraft, Peter A1 - Lawlor, Debbie A1 - Metspalu, Andres A1 - Pennell, Craig E A1 - Ridker, Paul M A1 - Snieder, Harold A1 - Sørensen, Thorkild I A A1 - Spector, Tim D A1 - Strachan, David P A1 - Uitterlinden, André G A1 - Wareham, Nicholas J A1 - Widen, Elisabeth A1 - Zygmunt, Marek A1 - Murray, Anna A1 - Easton, Douglas F A1 - Stefansson, Kari A1 - Murabito, Joanne M A1 - Ong, Ken K KW - Adolescent KW - Age Factors KW - Alleles KW - Body Mass Index KW - Breast Neoplasms KW - Cardiovascular Diseases KW - Child KW - Diabetes Mellitus, Type 2 KW - Europe KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genomic Imprinting KW - Humans KW - Hypothalamo-Hypophyseal System KW - Intercellular Signaling Peptides and Proteins KW - Male KW - Membrane Proteins KW - Menarche KW - Obesity KW - Ovary KW - Parents KW - Polymorphism, Single Nucleotide KW - Potassium Channels, Tandem Pore Domain KW - Proteins KW - Quantitative Trait Loci KW - Receptors, GABA-B KW - Receptors, Retinoic Acid KW - Ribonucleoproteins AB -

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

VL - 514 IS - 7520 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25231870?dopt=Abstract ER - TY - JOUR T1 - Platelet diameters in inherited thrombocytopenias: analysis of 376 patients with all known disorders. JF - Blood Y1 - 2014 A1 - Noris, Patrizia A1 - Biino, Ginevra A1 - Pecci, Alessandro A1 - Civaschi, Elisa A1 - Savoia, Anna A1 - Seri, Marco A1 - Melazzini, Federica A1 - Loffredo, Giuseppe A1 - Russo, Giovanna A1 - Bozzi, Valeria A1 - Notarangelo, Lucia Dora A1 - Gresele, Paolo A1 - Heller, Paula G A1 - Pujol-Moix, Núria A1 - Kunishima, Shinji A1 - Cattaneo, Marco A1 - Bussel, James A1 - De Candia, Erica A1 - Cagioni, Claudia A1 - Ramenghi, Ugo A1 - Barozzi, Serena A1 - Fabris, Fabrizio A1 - Balduini, Carlo L KW - Adolescent KW - Adult KW - Blood Platelets KW - Case-Control Studies KW - Cell Size KW - Child KW - Child, Preschool KW - Diagnosis, Differential KW - Female KW - Hearing Loss, Sensorineural KW - Humans KW - Infant KW - Male KW - Middle Aged KW - Molecular Motor Proteins KW - Mutation KW - Myosin Heavy Chains KW - Purpura, Thrombocytopenic, Idiopathic KW - Thrombocytopenia KW - Young Adult AB -

Abnormalities of platelet size are one of the distinguishing features of inherited thrombocytopenias (ITs), and evaluation of blood films is recommended as an essential step for differential diagnosis of these disorders. Nevertheless, what we presently know about this subject is derived mainly from anecdotal evidence. To improve knowledge in this field, we evaluated platelet size on blood films obtained from 376 patients with all 19 forms of IT identified so far and found that these conditions differ not only in mean platelet diameter, but also in platelet diameter distribution width and the percentage of platelets with increased or reduced diameters. On the basis of these findings, we propose a new classification of ITs according to platelet size. It distinguishes forms with giant platelets, with large platelets, with normal or slightly increased platelet size, and with normal or slightly decreased platelet size. We also measured platelet diameters in 87 patients with immune thrombocytopenia and identified cutoff values for mean platelet diameter and the percentage of platelets with increased or reduced size that have good diagnostic accuracy in differentiating ITs with giant platelets and with normal or slightly decreased platelet size from immune thrombocytopenia and all other forms of IT.

VL - 124 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24990887?dopt=Abstract ER - TY - JOUR T1 - A randomized trial of hyperimmune globulin to prevent congenital cytomegalovirus. JF - N Engl J Med Y1 - 2014 A1 - Revello, Maria Grazia A1 - Lazzarotto, Tiziana A1 - Guerra, Brunella A1 - Spinillo, Arsenio A1 - Ferrazzi, Enrico A1 - Kustermann, Alessandra A1 - Guaschino, Secondo A1 - Vergani, Patrizia A1 - Todros, Tullia A1 - Frusca, Tiziana A1 - Arossa, Alessia A1 - Furione, Milena A1 - Rognoni, Vanina A1 - Rizzo, Nicola A1 - Gabrielli, Liliana A1 - Klersy, Catherine A1 - Gerna, Giuseppe KW - Adult KW - Amniocentesis KW - Cytomegalovirus KW - Cytomegalovirus Infections KW - Female KW - Fetal Diseases KW - Humans KW - Immunoglobulins KW - Infectious Disease Transmission, Vertical KW - Pregnancy KW - Pregnancy Complications, Infectious AB -

BACKGROUND: Congenital infection with human cytomegalovirus (CMV) is a major cause of morbidity and mortality. In an uncontrolled study published in 2005, administration of CMV-specific hyperimmune globulin to pregnant women with primary CMV infection significantly reduced the rate of intrauterine transmission, from 40% to 16%.

METHODS: We evaluated the efficacy of hyperimmune globulin in a phase 2, randomized, placebo-controlled, double-blind study. A total of 124 pregnant women with primary CMV infection at 5 to 26 weeks of gestation were randomly assigned within 6 weeks after the presumed onset of infection to receive hyperimmune globulin or placebo every 4 weeks until 36 weeks of gestation or until detection of CMV in amniotic fluid. The primary end point was congenital infection diagnosed at birth or by means of amniocentesis.

RESULTS: A total of 123 women could be evaluated in the efficacy analysis (1 woman in the placebo group withdrew). The rate of congenital infection was 30% (18 fetuses or infants of 61 women) in the hyperimmune globulin group and 44% (27 fetuses or infants of 62 women) in the placebo group (a difference of 14 percentage points; 95% confidence interval, -3 to 31; P=0.13). There was no significant difference between the two groups or, within each group, between the women who transmitted the virus and those who did not, with respect to levels of virus-specific antibodies, T-cell-mediated immune response, or viral DNA in the blood. The clinical outcome of congenital infection at birth was similar in the two groups. The number of obstetrical adverse events was higher in the hyperimmune globulin group than in the placebo group (13% vs. 2%).

CONCLUSIONS: In this study involving 123 women who could be evaluated, treatment with hyperimmune globulin did not significantly modify the course of primary CMV infection during pregnancy. (Funded by Agenzia Italiana del Farmaco; CHIP ClinicalTrials.gov number, NCT00881517; EudraCT no. 2008-006560-11.).

VL - 370 IS - 14 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24693891?dopt=Abstract ER - TY - JOUR T1 - Spectrum of the mutations in Bernard-Soulier syndrome. JF - Hum Mutat Y1 - 2014 A1 - Savoia, Anna A1 - Kunishima, Shinji A1 - De Rocco, Daniela A1 - Zieger, Barbara A1 - Rand, Margaret L A1 - Pujol-Moix, Núria A1 - Caliskan, Umran A1 - Tokgoz, Huseyin A1 - Pecci, Alessandro A1 - Noris, Patrizia A1 - Srivastava, Alok A1 - Ward, Christopher A1 - Morel-Kopp, Marie-Christine A1 - Alessi, Marie-Christine A1 - Bellucci, Sylvia A1 - Beurrier, Philippe A1 - de Maistre, Emmanuel A1 - Favier, Rémi A1 - Hézard, Nathalie A1 - Hurtaud-Roux, Marie-Françoise A1 - Latger-Cannard, Véronique A1 - Lavenu-Bombled, Cécile A1 - Proulle, Valérie A1 - Meunier, Sandrine A1 - Négrier, Claude A1 - Nurden, Alan A1 - Randrianaivo, Hanitra A1 - Fabris, Fabrizio A1 - Platokouki, Helen A1 - Rosenberg, Nurit A1 - HadjKacem, Basma A1 - Heller, Paula G A1 - Karimi, Mehran A1 - Balduini, Carlo L A1 - Pastore, Annalisa A1 - Lanza, Francois KW - Alleles KW - Bernard-Soulier Syndrome KW - Databases, Nucleic Acid KW - Founder Effect KW - Genetic Variation KW - Humans KW - Mutation KW - Platelet Glycoprotein GPIb-IX Complex KW - Polymorphism, Single Nucleotide KW - von Willebrand Diseases KW - Web Browser AB -

Bernard-Soulier syndrome (BSS) is a rare autosomal recessive bleeding disorder characterized by defects of the GPIb-IX-V complex, a platelet receptor for von Willebrand factor (VWF). Most of the mutations identified in the genes encoding for the GP1BA (GPIbα), GP1BB (GPIbβ), and GP9 (GPIX) subunits prevent expression of the complex at the platelet membrane or more rarely its interaction with VWF. As a consequence, platelets are unable to adhere to the vascular subendothelium and agglutinate in response to ristocetin. In order to collect information on BSS patients, we established an International Consortium for the study of BSS, allowing us to enrol and genotype 132 families (56 previously unreported). With 79 additional families for which molecular data were gleaned from the literature, the 211 families characterized so far have mutations in the GP1BA (28%), GP1BB (28%), or GP9 (44%) genes. There is a wide spectrum of mutations with 112 different variants, including 22 novel alterations. Consistent with the rarity of the disease, 85% of the probands carry homozygous mutations with evidence of founder effects in some geographical areas. This overview provides the first global picture of the molecular basis of BSS and will lead to improve patient diagnosis and management.

VL - 35 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24934643?dopt=Abstract ER - TY - JOUR T1 - Trans-ethnic meta-analysis of white blood cell phenotypes. JF - Hum Mol Genet Y1 - 2014 A1 - Keller, Margaux F A1 - Reiner, Alexander P A1 - Okada, Yukinori A1 - van Rooij, Frank J A A1 - Johnson, Andrew D A1 - Chen, Ming-Huei A1 - Smith, Albert V A1 - Morris, Andrew P A1 - Tanaka, Toshiko A1 - Ferrucci, Luigi A1 - Zonderman, Alan B A1 - Lettre, Guillaume A1 - Harris, Tamara A1 - Garcia, Melissa A1 - Bandinelli, Stefania A1 - Qayyum, Rehan A1 - Yanek, Lisa R A1 - Becker, Diane M A1 - Becker, Lewis C A1 - Kooperberg, Charles A1 - Keating, Brendan A1 - Reis, Jared A1 - Tang, Hua A1 - Boerwinkle, Eric A1 - Kamatani, Yoichiro A1 - Matsuda, Koichi A1 - Kamatani, Naoyuki A1 - Nakamura, Yusuke A1 - Kubo, Michiaki A1 - Liu, Simin A1 - Dehghan, Abbas A1 - Felix, Janine F A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Franco, Oscar H A1 - Longo, Dan L A1 - Singleton, Andrew B A1 - Psaty, Bruce M A1 - Evans, Michelle K A1 - Cupples, L Adrienne A1 - Rotter, Jerome I A1 - O'Donnell, Christopher J A1 - Takahashi, Atsushi A1 - Wilson, James G A1 - Ganesh, Santhi K A1 - Nalls, Mike A KW - African Americans KW - Asian Continental Ancestry Group KW - Bayes Theorem KW - European Continental Ancestry Group KW - Genome, Human KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Leukocyte Count KW - Leukocytes KW - Linkage Disequilibrium KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci AB -

White blood cell (WBC) count is a common clinical measure used as a predictor of certain aspects of human health, including immunity and infection status. WBC count is also a complex trait that varies among individuals and ancestry groups. Differences in linkage disequilibrium structure and heterogeneity in allelic effects are expected to play a role in the associations observed between populations. Prior genome-wide association study (GWAS) meta-analyses have identified genomic loci associated with WBC and its subtypes, but much of the heritability of these phenotypes remains unexplained. Using GWAS summary statistics for over 50 000 individuals from three diverse populations (Japanese, African-American and European ancestry), a Bayesian model methodology was employed to account for heterogeneity between ancestry groups. This approach was used to perform a trans-ethnic meta-analysis of total WBC, neutrophil and monocyte counts. Ten previously known associations were replicated and six new loci were identified, including several regions harboring genes related to inflammation and immune cell function. Ninety-five percent credible interval regions were calculated to narrow the association signals and fine-map the putatively causal variants within loci. Finally, a conditional analysis was performed on the most significant SNPs identified by the trans-ethnic meta-analysis (MA), and nine secondary signals within loci previously associated with WBC or its subtypes were identified. This work illustrates the potential of trans-ethnic analysis and ascribes a critical role to multi-ethnic cohorts and consortia in exploring complex phenotypes with respect to variants that lie outside the European-biased GWAS pool.

VL - 23 IS - 25 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25096241?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. JF - Nat Genet Y1 - 2013 A1 - Köttgen, Anna A1 - Albrecht, Eva A1 - Teumer, Alexander A1 - Vitart, Veronique A1 - Krumsiek, Jan A1 - Hundertmark, Claudia A1 - Pistis, Giorgio A1 - Ruggiero, Daniela A1 - O'Seaghdha, Conall M A1 - Haller, Toomas A1 - Yang, Qiong A1 - Tanaka, Toshiko A1 - Johnson, Andrew D A1 - Kutalik, Zoltán A1 - Smith, Albert V A1 - Shi, Julia A1 - Struchalin, Maksim A1 - Middelberg, Rita P S A1 - Brown, Morris J A1 - Gaffo, Angelo L A1 - Pirastu, Nicola A1 - Li, Guo A1 - Hayward, Caroline A1 - Zemunik, Tatijana A1 - Huffman, Jennifer A1 - Yengo, Loic A1 - Zhao, Jing Hua A1 - Demirkan, Ayse A1 - Feitosa, Mary F A1 - Liu, Xuan A1 - Malerba, Giovanni A1 - Lopez, Lorna M A1 - van der Harst, Pim A1 - Li, Xinzhong A1 - Kleber, Marcus E A1 - Hicks, Andrew A A1 - Nolte, Ilja M A1 - Johansson, Åsa A1 - Murgia, Federico A1 - Wild, Sarah H A1 - Bakker, Stephan J L A1 - Peden, John F A1 - Dehghan, Abbas A1 - Steri, Maristella A1 - Tenesa, Albert A1 - Lagou, Vasiliki A1 - Salo, Perttu A1 - Mangino, Massimo A1 - Rose, Lynda M A1 - Lehtimäki, Terho A1 - Woodward, Owen M A1 - Okada, Yukinori A1 - Tin, Adrienne A1 - Müller, Christian A1 - Oldmeadow, Christopher A1 - Putku, Margus A1 - Czamara, Darina A1 - Kraft, Peter A1 - Frogheri, Laura A1 - Thun, Gian Andri A1 - Grotevendt, Anne A1 - Gislason, Gauti Kjartan A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - McArdle, Patrick A1 - Shuldiner, Alan R A1 - Boerwinkle, Eric A1 - Coresh, Josef A1 - Schmidt, Helena A1 - Schallert, Michael A1 - Martin, Nicholas G A1 - Montgomery, Grant W A1 - Kubo, Michiaki A1 - Nakamura, Yusuke A1 - Tanaka, Toshihiro A1 - Munroe, Patricia B A1 - Samani, Nilesh J A1 - Jacobs, David R A1 - Liu, Kiang A1 - d'Adamo, Pio A1 - Ulivi, Sheila A1 - Rotter, Jerome I A1 - Psaty, Bruce M A1 - Vollenweider, Peter A1 - Waeber, Gerard A1 - Campbell, Susan A1 - Devuyst, Olivier A1 - Navarro, Pau A1 - Kolcic, Ivana A1 - Hastie, Nicholas A1 - Balkau, Beverley A1 - Froguel, Philippe A1 - Esko, Tõnu A1 - Salumets, Andres A1 - Khaw, Kay Tee A1 - Langenberg, Claudia A1 - Wareham, Nicholas J A1 - Isaacs, Aaron A1 - Kraja, Aldi A1 - Zhang, Qunyuan A1 - Wild, Philipp S A1 - Scott, Rodney J A1 - Holliday, Elizabeth G A1 - Org, Elin A1 - Viigimaa, Margus A1 - Bandinelli, Stefania A1 - Metter, Jeffrey E A1 - Lupo, Antonio A1 - Trabetti, Elisabetta A1 - Sorice, Rossella A1 - Döring, Angela A1 - Lattka, Eva A1 - Strauch, Konstantin A1 - Theis, Fabian A1 - Waldenberger, Melanie A1 - Wichmann, H-Erich A1 - Davies, Gail A1 - Gow, Alan J A1 - Bruinenberg, Marcel A1 - Stolk, Ronald P A1 - Kooner, Jaspal S A1 - Zhang, Weihua A1 - Winkelmann, Bernhard R A1 - Boehm, Bernhard O A1 - Lucae, Susanne A1 - Penninx, Brenda W A1 - Smit, Johannes H A1 - Curhan, Gary A1 - Mudgal, Poorva A1 - Plenge, Robert M A1 - Portas, Laura A1 - Persico, Ivana A1 - Kirin, Mirna A1 - Wilson, James F A1 - Mateo Leach, Irene A1 - van Gilst, Wiek H A1 - Goel, Anuj A1 - Ongen, Halit A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Imboden, Medea A1 - von Eckardstein, Arnold A1 - Cucca, Francesco A1 - Nagaraja, Ramaiah A1 - Piras, Maria Grazia A1 - Nauck, Matthias A1 - Schurmann, Claudia A1 - Budde, Kathrin A1 - Ernst, Florian A1 - Farrington, Susan M A1 - Theodoratou, Evropi A1 - Prokopenko, Inga A1 - Stumvoll, Michael A1 - Jula, Antti A1 - Perola, Markus A1 - Salomaa, Veikko A1 - Shin, So-Youn A1 - Spector, Tim D A1 - Sala, Cinzia A1 - Ridker, Paul M A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Hengstenberg, Christian A1 - Nelson, Christopher P A1 - Meschia, James F A1 - Nalls, Michael A A1 - Sharma, Pankaj A1 - Singleton, Andrew B A1 - Kamatani, Naoyuki A1 - Zeller, Tanja A1 - Burnier, Michel A1 - Attia, John A1 - Laan, Maris A1 - Klopp, Norman A1 - Hillege, Hans L A1 - Kloiber, Stefan A1 - Choi, Hyon A1 - Pirastu, Mario A1 - Tore, Silvia A1 - Probst-Hensch, Nicole M A1 - Völzke, Henry A1 - Gudnason, Vilmundur A1 - Parsa, Afshin A1 - Schmidt, Reinhold A1 - Whitfield, John B A1 - Fornage, Myriam A1 - Gasparini, Paolo A1 - Siscovick, David S A1 - Polasek, Ozren A1 - Campbell, Harry A1 - Rudan, Igor A1 - Bouatia-Naji, Nabila A1 - Metspalu, Andres A1 - Loos, Ruth J F A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid B A1 - Ferrucci, Luigi A1 - Gambaro, Giovanni A1 - Deary, Ian J A1 - Wolffenbuttel, Bruce H R A1 - Chambers, John C A1 - März, Winfried A1 - Pramstaller, Peter P A1 - Snieder, Harold A1 - Gyllensten, Ulf A1 - Wright, Alan F A1 - Navis, Gerjan A1 - Watkins, Hugh A1 - Witteman, Jacqueline C M A1 - Sanna, Serena A1 - Schipf, Sabine A1 - Dunlop, Malcolm G A1 - Tönjes, Anke A1 - Ripatti, Samuli A1 - Soranzo, Nicole A1 - Toniolo, Daniela A1 - Chasman, Daniel I A1 - Raitakari, Olli A1 - Kao, W H Linda A1 - Ciullo, Marina A1 - Fox, Caroline S A1 - Caulfield, Mark A1 - Bochud, Murielle A1 - Gieger, Christian KW - Analysis of Variance KW - European Continental Ancestry Group KW - Gene Frequency KW - Genetic Loci KW - Genome-Wide Association Study KW - Glucose KW - Gout KW - Humans KW - Inhibins KW - Polymorphism, Single Nucleotide KW - Signal Transduction KW - Uric Acid AB -

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

VL - 45 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23263486?dopt=Abstract ER - TY - JOUR T1 - Accuracy of diagnostic antibody tests for coeliac disease in children: summary of an evidence report. JF - J Pediatr Gastroenterol Nutr Y1 - 2012 A1 - Giersiepen, Klaus A1 - Lelgemann, Monika A1 - Stuhldreher, Nina A1 - Ronfani, Luca A1 - Husby, Steffen A1 - Koletzko, Sibylle A1 - Korponay-Szabó, Ilma R KW - Autoantibodies KW - Biological Markers KW - Celiac Disease KW - Child KW - Gliadin KW - GTP-Binding Proteins KW - Humans KW - Immunoglobulin A KW - Immunoglobulin G KW - Point-of-Care Systems KW - Sensitivity and Specificity KW - Transglutaminases AB -

OBJECTIVE: The aim of this study was to summarise the evidence from 2004 to September 2009 on the performance of laboratory-based serological and point of care (POC) tests for diagnosing coeliac disease (CD) in children using histology as reference standard.

PATIENTS AND METHODS: We searched MEDLINE and EMBASE for studies reporting on children for tests based on IgA and IgG anti-gliadin (AGA), endomysial (EmA), anti-transglutaminase-2 (TG2), and anti-deamidated gliadin peptides (DGP) antibodies or POC tests. For inclusion, histological analysis of duodenal biopsies and sensitivity and specificity for index tests had to be reported. Data were pooled and summary measures calculated for sensitivity, specificity, positive and negative likelihood ratios ("LR+", "LR-"), and diagnostic odds ratios (DOR). In case of elevated statistical heterogeneity, studies reaching 90% sensitivity or specificity were reported.

RESULTS: A total of 2510 articles were reviewed; 16 entered meta-analysis, reporting on 3110 patients (1876 with CD, 1234 without CD). For IgA-EmA, sensitivity was ≥90% in 7/11 studies and pooled specificity 98.2%. For IgA-anti-TG2, 11/15 studies yielded sensitivities ≥90% and 13/15 specificities ≥90%. For IgA-DGP, sensitivity ranged between 80.7% and 95.1% (specificity 86.3%-93.1%); for IgG-DGP between 80.1% and 98.6% (specificity 86.0-96.9%). IgA-EmA had the highest pooled DOR (554) and LR+ (31.8) for a laboratory test, followed by IgA-anti-TG2, IgG-DGP, IgA-DGP and IgA-AGA. POC tests showed a pooled sensitivity of 96.4% for IgA-TG2 (specificity 97.7%).

CONCLUSIONS: IgA-EmA and IgA-anti-TG2 tests appear highly accurate to diagnose CD. IgG-anti-DGP tests may help in excluding CD. IgA-AGA and IgA-DGP tests show inferior accuracy. POC tests may achieve high accuracy in the hands of experienced readers, but IgA-anti-TG2/EmA were superior.

VL - 54 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22266486?dopt=Abstract ER - TY - JOUR T1 - Coeliac disease diagnosis: ESPGHAN 1990 criteria or need for a change? Results of a questionnaire. JF - J Pediatr Gastroenterol Nutr Y1 - 2012 A1 - Ribes-Koninckx, C A1 - Mearin, M L A1 - Korponay-Szabó, I R A1 - Shamir, R A1 - Husby, S A1 - Ventura, A A1 - Branski, D A1 - Catassi, C A1 - Koletzko, S A1 - Mäki, M A1 - Troncone, R A1 - Zimmer, K P KW - Adolescent KW - Adult KW - Biopsy KW - Celiac Disease KW - Child KW - Child, Preschool KW - Glutens KW - Guideline Adherence KW - Guidelines as Topic KW - Health Care Surveys KW - Humans KW - Immunoglobulin A KW - Intestine, Small KW - Physician's Practice Patterns KW - Questionnaires KW - Societies, Medical KW - Transglutaminases KW - Young Adult AB -

BACKGROUND AND OBJECTIVES: A revision of criteria for diagnosing coeliac disease (CD) is being conducted by The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). In parallel, we have performed a survey aimed to evaluate present practices for CD among paediatric gastroenterologists and to learn their views on the need for modification of present criteria for CD diagnosis.

PATIENTS AND METHODS: Questionnaires were distributed to experienced paediatric gastroenterologists (ESPGHAN members) via the Internet.

RESULTS: Overall, 95 valid questionnaires were available for analysis, pertaining to 28 different countries, with the majority of responders treating patients with CD for >15 years. Only about 12% of the responders comply with present criteria, noncompliance being related mainly to the challenge policy. Approximately 90% request a revision and modification of the present criteria. Forty-four percent want to omit the small bowel biopsy in symptomatic children with positive anti-tissue transglutaminase immunoglobulin (Ig) A or endomysial IgA antibodies, especially if they are DQ2/DQ8 positive. For silent cases detected by screening with convincingly positive anti-tissue transglutaminase IgA or EMA IgA, about 30% consider that no small bowel biopsy should be required in selected cases. Adding human leukocyte antigen typing in the diagnostic workup was asked for by 42% of the responders. As for gluten challenge, a new policy is advocated restricting its obligation to cases whenever the diagnosis is doubtful or unclear.

CONCLUSIONS: Based on these opinions, revision of the ESPGHAN criteria for diagnosing CD is urgently needed.

VL - 54 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21716133?dopt=Abstract ER - TY - JOUR T1 - European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. JF - J Pediatr Gastroenterol Nutr Y1 - 2012 A1 - Husby, S A1 - Koletzko, S A1 - Korponay-Szabó, I R A1 - Mearin, M L A1 - Phillips, A A1 - Shamir, R A1 - Troncone, R A1 - Giersiepen, K A1 - Branski, D A1 - Catassi, C A1 - Lelgeman, M A1 - Mäki, M A1 - Ribes-Koninckx, C A1 - Ventura, A A1 - Zimmer, K P KW - Adolescent KW - Celiac Disease KW - Child KW - Duodenum KW - HLA-DQ Antigens KW - Humans KW - Immunoglobulin A KW - Transglutaminases AB -

OBJECTIVE: Diagnostic criteria for coeliac disease (CD) from the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) were published in 1990. Since then, the autoantigen in CD, tissue transglutaminase, has been identified; the perception of CD has changed from that of a rather uncommon enteropathy to a common multiorgan disease strongly dependent on the haplotypes human leukocyte antigen (HLA)-DQ2 and HLA-DQ8; and CD-specific antibody tests have improved.

METHODS: A panel of 17 experts defined CD and developed new diagnostic criteria based on the Delphi process. Two groups of patients were defined with different diagnostic approaches to diagnose CD: children with symptoms suggestive of CD (group 1) and asymptomatic children at increased risk for CD (group 2). The 2004 National Institutes of Health/Agency for Healthcare Research and Quality report and a systematic literature search on antibody tests for CD in paediatric patients covering the years 2004 to 2009 was the basis for the evidence-based recommendations on CD-specific antibody testing.

RESULTS: In group 1, the diagnosis of CD is based on symptoms, positive serology, and histology that is consistent with CD. If immunoglobulin A anti-tissue transglutaminase type 2 antibody titers are high (>10 times the upper limit of normal), then the option is to diagnose CD without duodenal biopsies by applying a strict protocol with further laboratory tests. In group 2, the diagnosis of CD is based on positive serology and histology. HLA-DQ2 and HLA-DQ8 testing is valuable because CD is unlikely if both haplotypes are negative.

CONCLUSIONS: The aim of the new guidelines was to achieve a high diagnostic accuracy and to reduce the burden for patients and their families. The performance of these guidelines in clinical practice should be evaluated prospectively.

VL - 54 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22197856?dopt=Abstract ER - TY - JOUR T1 - Evidence of inbreeding depression on human height. JF - PLoS Genet Y1 - 2012 A1 - McQuillan, Ruth A1 - Eklund, Niina A1 - Pirastu, Nicola A1 - Kuningas, Maris A1 - McEvoy, Brian P A1 - Esko, Tõnu A1 - Corre, Tanguy A1 - Davies, Gail A1 - Kaakinen, Marika A1 - Lyytikäinen, Leo-Pekka A1 - Kristiansson, Kati A1 - Havulinna, Aki S A1 - Gögele, Martin A1 - Vitart, Veronique A1 - Tenesa, Albert A1 - Aulchenko, Yurii A1 - Hayward, Caroline A1 - Johansson, Åsa A1 - Boban, Mladen A1 - Ulivi, Sheila A1 - Robino, Antonietta A1 - Boraska, Vesna A1 - Igl, Wilmar A1 - Wild, Sarah H A1 - Zgaga, Lina A1 - Amin, Najaf A1 - Theodoratou, Evropi A1 - Polasek, Ozren A1 - Girotto, Giorgia A1 - Lopez, Lorna M A1 - Sala, Cinzia A1 - Lahti, Jari A1 - Laatikainen, Tiina A1 - Prokopenko, Inga A1 - Kals, Mart A1 - Viikari, Jorma A1 - Yang, Jian A1 - Pouta, Anneli A1 - Estrada, Karol A1 - Hofman, Albert A1 - Freimer, Nelson A1 - Martin, Nicholas G A1 - Kähönen, Mika A1 - Milani, Lili A1 - Heliövaara, Markku A1 - Vartiainen, Erkki A1 - Räikkönen, Katri A1 - Masciullo, Corrado A1 - Starr, John M A1 - Hicks, Andrew A A1 - Esposito, Laura A1 - Kolcic, Ivana A1 - Farrington, Susan M A1 - Oostra, Ben A1 - Zemunik, Tatijana A1 - Campbell, Harry A1 - Kirin, Mirna A1 - Pehlic, Marina A1 - Faletra, Flavio A1 - Porteous, David A1 - Pistis, Giorgio A1 - Widen, Elisabeth A1 - Salomaa, Veikko A1 - Koskinen, Seppo A1 - Fischer, Krista A1 - Lehtimäki, Terho A1 - Heath, Andrew A1 - McCarthy, Mark I A1 - Rivadeneira, Fernando A1 - Montgomery, Grant W A1 - Tiemeier, Henning A1 - Hartikainen, Anna-Liisa A1 - Madden, Pamela A F A1 - d'Adamo, Pio A1 - Hastie, Nicholas D A1 - Gyllensten, Ulf A1 - Wright, Alan F A1 - van Duijn, Cornelia M A1 - Dunlop, Malcolm A1 - Rudan, Igor A1 - Gasparini, Paolo A1 - Pramstaller, Peter P A1 - Deary, Ian J A1 - Toniolo, Daniela A1 - Eriksson, Johan G A1 - Jula, Antti A1 - Raitakari, Olli T A1 - Metspalu, Andres A1 - Perola, Markus A1 - Järvelin, Marjo-Riitta A1 - Uitterlinden, André A1 - Visscher, Peter M A1 - Wilson, James F KW - Adult KW - Aged KW - Body Height KW - Consanguinity KW - Databases, Genetic KW - Family KW - Female KW - Genes, Recessive KW - Genetic Heterogeneity KW - Genome-Wide Association Study KW - Homozygote KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Quantitative Trait, Heritable AB -

Stature is a classical and highly heritable complex trait, with 80%-90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (χ(2) = 83.89, df = 1; p = 5.2 × 10(-20)). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.

VL - 8 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22829771?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association and functional follow-up reveals new loci for kidney function. JF - PLoS Genet Y1 - 2012 A1 - Pattaro, Cristian A1 - Köttgen, Anna A1 - Teumer, Alexander A1 - Garnaas, Maija A1 - Böger, Carsten A A1 - Fuchsberger, Christian A1 - Olden, Matthias A1 - Chen, Ming-Huei A1 - Tin, Adrienne A1 - Taliun, Daniel A1 - Li, Man A1 - Gao, Xiaoyi A1 - Gorski, Mathias A1 - Yang, Qiong A1 - Hundertmark, Claudia A1 - Foster, Meredith C A1 - O'Seaghdha, Conall M A1 - Glazer, Nicole A1 - Isaacs, Aaron A1 - Liu, Ching-Ti A1 - Smith, Albert V A1 - O'Connell, Jeffrey R A1 - Struchalin, Maksim A1 - Tanaka, Toshiko A1 - Li, Guo A1 - Johnson, Andrew D A1 - Gierman, Hinco J A1 - Feitosa, Mary A1 - Hwang, Shih-Jen A1 - Atkinson, Elizabeth J A1 - Lohman, Kurt A1 - Cornelis, Marilyn C A1 - Johansson, Åsa A1 - Tönjes, Anke A1 - Dehghan, Abbas A1 - Chouraki, Vincent A1 - Holliday, Elizabeth G A1 - Sorice, Rossella A1 - Kutalik, Zoltán A1 - Lehtimäki, Terho A1 - Esko, Tõnu A1 - Deshmukh, Harshal A1 - Ulivi, Sheila A1 - Chu, Audrey Y A1 - Murgia, Federico A1 - Trompet, Stella A1 - Imboden, Medea A1 - Kollerits, Barbara A1 - Pistis, Giorgio A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Mitchell, Braxton D A1 - Boerwinkle, Eric A1 - Schmidt, Helena A1 - Cavalieri, Margherita A1 - Rao, Madhumathi A1 - Hu, Frank B A1 - Demirkan, Ayse A1 - Oostra, Ben A A1 - de Andrade, Mariza A1 - Turner, Stephen T A1 - Ding, Jingzhong A1 - Andrews, Jeanette S A1 - Freedman, Barry I A1 - Koenig, Wolfgang A1 - Illig, Thomas A1 - Döring, Angela A1 - Wichmann, H-Erich A1 - Kolcic, Ivana A1 - Zemunik, Tatijana A1 - Boban, Mladen A1 - Minelli, Cosetta A1 - Wheeler, Heather E A1 - Igl, Wilmar A1 - Zaboli, Ghazal A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Campbell, Harry A1 - Ellinghaus, David A1 - Nöthlings, Ute A1 - Jacobs, Gunnar A1 - Biffar, Reiner A1 - Endlich, Karlhans A1 - Ernst, Florian A1 - Homuth, Georg A1 - Kroemer, Heyo K A1 - Nauck, Matthias A1 - Stracke, Sylvia A1 - Völker, Uwe A1 - Völzke, Henry A1 - Kovacs, Peter A1 - Stumvoll, Michael A1 - Mägi, Reedik A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Aulchenko, Yurii S A1 - Polasek, Ozren A1 - Hastie, Nick A1 - Vitart, Veronique A1 - Helmer, Catherine A1 - Wang, Jie Jin A1 - Ruggiero, Daniela A1 - Bergmann, Sven A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Nikopensius, Tiit A1 - Province, Michael A1 - Ketkar, Shamika A1 - Colhoun, Helen A1 - Doney, Alex A1 - Robino, Antonietta A1 - Giulianini, Franco A1 - Krämer, Bernhard K A1 - Portas, Laura A1 - Ford, Ian A1 - Buckley, Brendan M A1 - Adam, Martin A1 - Thun, Gian-Andri A1 - Paulweber, Bernhard A1 - Haun, Margot A1 - Sala, Cinzia A1 - Metzger, Marie A1 - Mitchell, Paul A1 - Ciullo, Marina A1 - Kim, Stuart K A1 - Vollenweider, Peter A1 - Raitakari, Olli A1 - Metspalu, Andres A1 - Palmer, Colin A1 - Gasparini, Paolo A1 - Pirastu, Mario A1 - Jukema, J Wouter A1 - Probst-Hensch, Nicole M A1 - Kronenberg, Florian A1 - Toniolo, Daniela A1 - Gudnason, Vilmundur A1 - Shuldiner, Alan R A1 - Coresh, Josef A1 - Schmidt, Reinhold A1 - Ferrucci, Luigi A1 - Siscovick, David S A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Curhan, Gary C A1 - Rudan, Igor A1 - Gyllensten, Ulf A1 - Wilson, James F A1 - Franke, Andre A1 - Pramstaller, Peter P A1 - Rettig, Rainer A1 - Prokopenko, Inga A1 - Witteman, Jacqueline C M A1 - Hayward, Caroline A1 - Ridker, Paul A1 - Parsa, Afshin A1 - Bochud, Murielle A1 - Heid, Iris M A1 - Goessling, Wolfram A1 - Chasman, Daniel I A1 - Kao, W H Linda A1 - Fox, Caroline S KW - African Americans KW - Aged KW - Animals KW - Caspase 9 KW - Cyclin-Dependent Kinases KW - DEAD-box RNA Helicases KW - DNA Helicases KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Gene Knockdown Techniques KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Phosphoric Diester Hydrolases KW - Zebrafish AB -

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

VL - 8 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22479191?dopt=Abstract ER - TY - JOUR T1 - Gluten-dependent intestinal autoimmune response. JF - Curr Pharm Des Y1 - 2012 A1 - Korponay-Szabó, Ilma Rita A1 - Simon-Vecsei, Zsafia A1 - De Leo, Luigina A1 - Not, Tarcisio KW - Animals KW - Autoantibodies KW - Celiac Disease KW - Genetic Predisposition to Disease KW - Gliadin KW - Glutens KW - Humans KW - Intestinal Mucosa KW - T-Lymphocytes KW - Transglutaminases AB -

Celiac disease is a multi-systemic autoimmune disease of the small bowel induced by gluten in genetically predisposed subjects. Highly specific and gluten-dependent production of auto-antibodies targeting self-proteins of the transglutaminase family occurs in the intestinal mucosa. These anti-transglutaminase antibodies are found deposited in intestinal and extra-intestinal tissue where they might exert biological effects, together with the intestinal mucosal gliadin-specific T lymphocytes. We conducted a brief review on antitransglutaminase antibodies effects, discussing their roles in the pathogenesis of several clinical manifestations of celiac disease.

VL - 18 IS - 35 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22726113?dopt=Abstract ER - TY - JOUR T1 - Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function. JF - Hum Mol Genet Y1 - 2012 A1 - Chasman, Daniel I A1 - Fuchsberger, Christian A1 - Pattaro, Cristian A1 - Teumer, Alexander A1 - Böger, Carsten A A1 - Endlich, Karlhans A1 - Olden, Matthias A1 - Chen, Ming-Huei A1 - Tin, Adrienne A1 - Taliun, Daniel A1 - Li, Man A1 - Gao, Xiaoyi A1 - Gorski, Mathias A1 - Yang, Qiong A1 - Hundertmark, Claudia A1 - Foster, Meredith C A1 - O'Seaghdha, Conall M A1 - Glazer, Nicole A1 - Isaacs, Aaron A1 - Liu, Ching-Ti A1 - Smith, Albert V A1 - O'Connell, Jeffrey R A1 - Struchalin, Maksim A1 - Tanaka, Toshiko A1 - Li, Guo A1 - Johnson, Andrew D A1 - Gierman, Hinco J A1 - Feitosa, Mary F A1 - Hwang, Shih-Jen A1 - Atkinson, Elizabeth J A1 - Lohman, Kurt A1 - Cornelis, Marilyn C A1 - Johansson, Åsa A1 - Tönjes, Anke A1 - Dehghan, Abbas A1 - Lambert, Jean-Charles A1 - Holliday, Elizabeth G A1 - Sorice, Rossella A1 - Kutalik, Zoltán A1 - Lehtimäki, Terho A1 - Esko, Tõnu A1 - Deshmukh, Harshal A1 - Ulivi, Sheila A1 - Chu, Audrey Y A1 - Murgia, Federico A1 - Trompet, Stella A1 - Imboden, Medea A1 - Coassin, Stefan A1 - Pistis, Giorgio A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Mitchell, Braxton D A1 - Boerwinkle, Eric A1 - Schmidt, Helena A1 - Cavalieri, Margherita A1 - Rao, Madhumathi A1 - Hu, Frank A1 - Demirkan, Ayse A1 - Oostra, Ben A A1 - de Andrade, Mariza A1 - Turner, Stephen T A1 - Ding, Jingzhong A1 - Andrews, Jeanette S A1 - Freedman, Barry I A1 - Giulianini, Franco A1 - Koenig, Wolfgang A1 - Illig, Thomas A1 - Meisinger, Christa A1 - Gieger, Christian A1 - Zgaga, Lina A1 - Zemunik, Tatijana A1 - Boban, Mladen A1 - Minelli, Cosetta A1 - Wheeler, Heather E A1 - Igl, Wilmar A1 - Zaboli, Ghazal A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Campbell, Harry A1 - Ellinghaus, David A1 - Nöthlings, Ute A1 - Jacobs, Gunnar A1 - Biffar, Reiner A1 - Ernst, Florian A1 - Homuth, Georg A1 - Kroemer, Heyo K A1 - Nauck, Matthias A1 - Stracke, Sylvia A1 - Völker, Uwe A1 - Völzke, Henry A1 - Kovacs, Peter A1 - Stumvoll, Michael A1 - Mägi, Reedik A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Aulchenko, Yurii S A1 - Polasek, Ozren A1 - Hastie, Nick A1 - Vitart, Veronique A1 - Helmer, Catherine A1 - Wang, Jie Jin A1 - Stengel, Bénédicte A1 - Ruggiero, Daniela A1 - Bergmann, Sven A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Nikopensius, Tiit A1 - Province, Michael A1 - Ketkar, Shamika A1 - Colhoun, Helen A1 - Doney, Alex A1 - Robino, Antonietta A1 - Krämer, Bernhard K A1 - Portas, Laura A1 - Ford, Ian A1 - Buckley, Brendan M A1 - Adam, Martin A1 - Thun, Gian-Andri A1 - Paulweber, Bernhard A1 - Haun, Margot A1 - Sala, Cinzia A1 - Mitchell, Paul A1 - Ciullo, Marina A1 - Kim, Stuart K A1 - Vollenweider, Peter A1 - Raitakari, Olli A1 - Metspalu, Andres A1 - Palmer, Colin A1 - Gasparini, Paolo A1 - Pirastu, Mario A1 - Jukema, J Wouter A1 - Probst-Hensch, Nicole M A1 - Kronenberg, Florian A1 - Toniolo, Daniela A1 - Gudnason, Vilmundur A1 - Shuldiner, Alan R A1 - Coresh, Josef A1 - Schmidt, Reinhold A1 - Ferrucci, Luigi A1 - Siscovick, David S A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid B A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Curhan, Gary C A1 - Rudan, Igor A1 - Gyllensten, Ulf A1 - Wilson, James F A1 - Franke, Andre A1 - Pramstaller, Peter P A1 - Rettig, Rainer A1 - Prokopenko, Inga A1 - Witteman, Jacqueline A1 - Hayward, Caroline A1 - Ridker, Paul M A1 - Parsa, Afshin A1 - Bochud, Murielle A1 - Heid, Iris M A1 - Kao, W H Linda A1 - Fox, Caroline S A1 - Köttgen, Anna KW - Amino Acid Transport Systems, Basic KW - Antigens, CD98 Heavy Chain KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Inhibin-beta Subunits KW - Intracellular Signaling Peptides and Proteins KW - Low Density Lipoprotein Receptor-Related Protein-2 KW - Membrane Proteins KW - Polymorphism, Single Nucleotide AB -

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10(-4)-2.2 × 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.

VL - 21 IS - 24 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22962313?dopt=Abstract ER - TY - JOUR T1 - Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. JF - Nat Genet Y1 - 2012 A1 - Stolk, Lisette A1 - Perry, John R B A1 - Chasman, Daniel I A1 - He, Chunyan A1 - Mangino, Massimo A1 - Sulem, Patrick A1 - Barbalic, Maja A1 - Broer, Linda A1 - Byrne, Enda M A1 - Ernst, Florian A1 - Esko, Tõnu A1 - Franceschini, Nora A1 - Gudbjartsson, Daniel F A1 - Hottenga, Jouke-Jan A1 - Kraft, Peter A1 - McArdle, Patrick F A1 - Porcu, Eleonora A1 - Shin, So-Youn A1 - Smith, Albert V A1 - van Wingerden, Sophie A1 - Zhai, Guangju A1 - Zhuang, Wei V A1 - Albrecht, Eva A1 - Alizadeh, Behrooz Z A1 - Aspelund, Thor A1 - Bandinelli, Stefania A1 - Lauc, Lovorka Barac A1 - Beckmann, Jacques S A1 - Boban, Mladen A1 - Boerwinkle, Eric A1 - Broekmans, Frank J A1 - Burri, Andrea A1 - Campbell, Harry A1 - Chanock, Stephen J A1 - Chen, Constance A1 - Cornelis, Marilyn C A1 - Corre, Tanguy A1 - Coviello, Andrea D A1 - d'Adamo, Pio A1 - Davies, Gail A1 - de Faire, Ulf A1 - de Geus, Eco J C A1 - Deary, Ian J A1 - Dedoussis, George V Z A1 - Deloukas, Panagiotis A1 - Ebrahim, Shah A1 - Eiriksdottir, Gudny A1 - Emilsson, Valur A1 - Eriksson, Johan G A1 - Fauser, Bart C J M A1 - Ferreli, Liana A1 - Ferrucci, Luigi A1 - Fischer, Krista A1 - Folsom, Aaron R A1 - Garcia, Melissa E A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Glazer, Nicole A1 - Grobbee, Diederick E A1 - Hall, Per A1 - Haller, Toomas A1 - Hankinson, Susan E A1 - Hass, Merli A1 - Hayward, Caroline A1 - Heath, Andrew C A1 - Hofman, Albert A1 - Ingelsson, Erik A1 - Janssens, A Cecile J W A1 - Johnson, Andrew D A1 - Karasik, David A1 - Kardia, Sharon L R A1 - Keyzer, Jules A1 - Kiel, Douglas P A1 - Kolcic, Ivana A1 - Kutalik, Zoltán A1 - Lahti, Jari A1 - Lai, Sandra A1 - Laisk, Triin A1 - Laven, Joop S E A1 - Lawlor, Debbie A A1 - Liu, Jianjun A1 - Lopez, Lorna M A1 - Louwers, Yvonne V A1 - Magnusson, Patrik K E A1 - Marongiu, Mara A1 - Martin, Nicholas G A1 - Klaric, Irena Martinovic A1 - Masciullo, Corrado A1 - McKnight, Barbara A1 - Medland, Sarah E A1 - Melzer, David A1 - Mooser, Vincent A1 - Navarro, Pau A1 - Newman, Anne B A1 - Nyholt, Dale R A1 - Onland-Moret, N Charlotte A1 - Palotie, Aarno A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Pedersen, Nancy L A1 - Peeters, Petra H M A1 - Pistis, Giorgio A1 - Plump, Andrew S A1 - Polasek, Ozren A1 - Pop, Victor J M A1 - Psaty, Bruce M A1 - Räikkönen, Katri A1 - Rehnberg, Emil A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Sala, Cinzia A1 - Salumets, Andres A1 - Scuteri, Angelo A1 - Singleton, Andrew A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Soranzo, Nicole A1 - Stacey, Simon N A1 - Starr, John M A1 - Stathopoulou, Maria G A1 - Stirrups, Kathleen A1 - Stolk, Ronald P A1 - Styrkarsdottir, Unnur A1 - Sun, Yan V A1 - Tenesa, Albert A1 - Thorand, Barbara A1 - Toniolo, Daniela A1 - Tryggvadottir, Laufey A1 - Tsui, Kim A1 - Ulivi, Sheila A1 - van Dam, Rob M A1 - van der Schouw, Yvonne T A1 - van Gils, Carla H A1 - van Nierop, Peter A1 - Vink, Jacqueline M A1 - Visscher, Peter M A1 - Voorhuis, Marlies A1 - Waeber, Gerard A1 - Wallaschofski, Henri A1 - Wichmann, H Erich A1 - Widen, Elisabeth A1 - Wijnands-van Gent, Colette J M A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Wolffenbuttel, Bruce H R A1 - Wright, Alan F A1 - Yerges-Armstrong, Laura M A1 - Zemunik, Tatijana A1 - Zgaga, Lina A1 - Zillikens, M Carola A1 - Zygmunt, Marek A1 - Arnold, Alice M A1 - Boomsma, Dorret I A1 - Buring, Julie E A1 - Crisponi, Laura A1 - Demerath, Ellen W A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hu, Frank B A1 - Hunter, David J A1 - Launer, Lenore J A1 - Metspalu, Andres A1 - Montgomery, Grant W A1 - Oostra, Ben A A1 - Ridker, Paul M A1 - Sanna, Serena A1 - Schlessinger, David A1 - Spector, Tim D A1 - Stefansson, Kari A1 - Streeten, Elizabeth A A1 - Thorsteinsdottir, Unnur A1 - Uda, Manuela A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Völzke, Henry A1 - Murray, Anna A1 - Murabito, Joanne M A1 - Visser, Jenny A A1 - Lunetta, Kathryn L KW - Age Factors KW - DNA Helicases KW - DNA Primase KW - DNA Repair KW - DNA Repair Enzymes KW - DNA-Directed DNA Polymerase KW - European Continental Ancestry Group KW - Exodeoxyribonucleases KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Immunity KW - Menopause KW - Polymorphism, Single Nucleotide KW - Proteins AB -

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

VL - 44 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22267201?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations. JF - Nat Genet Y1 - 2012 A1 - Okada, Yukinori A1 - Sim, Xueling A1 - Go, Min Jin A1 - Wu, Jer-Yuarn A1 - Gu, Dongfeng A1 - Takeuchi, Fumihiko A1 - Takahashi, Atsushi A1 - Maeda, Shiro A1 - Tsunoda, Tatsuhiko A1 - Chen, Peng A1 - Lim, Su-Chi A1 - Wong, Tien-Yin A1 - Liu, Jianjun A1 - Young, Terri L A1 - Aung, Tin A1 - Seielstad, Mark A1 - Teo, Yik-Ying A1 - Kim, Young Jin A1 - Lee, Jong-Young A1 - Han, Bok-Ghee A1 - Kang, Daehee A1 - Chen, Chien-Hsiun A1 - Tsai, Fuu-Jen A1 - Chang, Li-Ching A1 - Fann, S-J Cathy A1 - Mei, Hao A1 - Rao, Dabeeru C A1 - Hixson, James E A1 - Chen, Shufeng A1 - Katsuya, Tomohiro A1 - Isono, Masato A1 - Ogihara, Toshio A1 - Chambers, John C A1 - Zhang, Weihua A1 - Kooner, Jaspal S A1 - Albrecht, Eva A1 - Yamamoto, Kazuhiko A1 - Kubo, Michiaki A1 - Nakamura, Yusuke A1 - Kamatani, Naoyuki A1 - Kato, Norihiro A1 - He, Jiang A1 - Chen, Yuan-Tsong A1 - Cho, Yoon Shin A1 - Tai, E-Shyong A1 - Tanaka, Toshihiro KW - Asian Continental Ancestry Group KW - Blood Urea Nitrogen KW - Cohort Studies KW - Creatinine KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Polymorphism, Single Nucleotide KW - Renal Insufficiency, Chronic KW - Uric Acid AB -

Chronic kidney disease (CKD), impairment of kidney function, is a serious public health problem, and the assessment of genetic factors influencing kidney function has substantial clinical relevance. Here, we report a meta-analysis of genome-wide association studies for kidney function-related traits, including 71,149 east Asian individuals from 18 studies in 11 population-, hospital- or family-based cohorts, conducted as part of the Asian Genetic Epidemiology Network (AGEN). Our meta-analysis identified 17 loci newly associated with kidney function-related traits, including the concentrations of blood urea nitrogen, uric acid and serum creatinine and estimated glomerular filtration rate based on serum creatinine levels (eGFRcrea) (P < 5.0 × 10(-8)). We further examined these loci with in silico replication in individuals of European ancestry from the KidneyGen, CKDGen and GUGC consortia, including a combined total of ∼110,347 individuals. We identify pleiotropic associations among these loci with kidney function-related traits and risk of CKD. These findings provide new insights into the genetics of kidney function.

VL - 44 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22797727?dopt=Abstract ER - TY - JOUR T1 - The negative prognostic value of TRAIL overexpression in oral squamous cell carcinomas does not preclude the potential therapeutic use of recombinant TRAIL. JF - Invest New Drugs Y1 - 2012 A1 - Carinci, Francesco A1 - Monasta, Lorenzo A1 - Rubini, Corrado A1 - Stramazzotti, Daniela A1 - Palmieri, Annalisa A1 - Melloni, Elisabetta A1 - Knowles, Alex A1 - Ronfani, Luca A1 - Zauli, Giorgio A1 - Secchiero, Paola KW - Adult KW - Aged KW - Aged, 80 and over KW - Antineoplastic Agents KW - Apoptosis KW - Carcinoma, Squamous Cell KW - Female KW - Flow Cytometry KW - HL-60 Cells KW - Humans KW - Immunohistochemistry KW - Male KW - Middle Aged KW - Mouth Neoplasms KW - Predictive Value of Tests KW - Prognosis KW - Proportional Hazards Models KW - Recombinant Proteins KW - Risk Assessment KW - Risk Factors KW - Survival Analysis KW - TNF-Related Apoptosis-Inducing Ligand KW - Tumor Markers, Biological KW - Up-Regulation KW - Young Adult VL - 30 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21086019?dopt=Abstract ER - TY - JOUR T1 - New insights in the sugarcane transcriptome responding to drought stress as revealed by superSAGE. JF - ScientificWorldJournal Y1 - 2012 A1 - Kido, Éderson Akio A1 - Ferreira Neto, José Ribamar Costa A1 - Silva, Roberta Lane de Oliveira A1 - Pandolfi, Valesca A1 - Guimarães, Ana Carolina Ribeiro A1 - Veiga, Daniela Truffi A1 - Chabregas, Sabrina Moutinho A1 - Crovella, Sergio A1 - Benko-Iseppon, Ana Maria KW - Droughts KW - Gene Expression Profiling KW - Heat-Shock Response KW - Plant Proteins KW - Saccharum KW - Transcriptome AB -

In the scope of the present work, four SuperSAGE libraries have been generated, using bulked root tissues from four drought-tolerant accessions as compared with four bulked sensitive genotypes, aiming to generate a panel of differentially expressed stress-responsive genes. Both groups were submitted to 24 hours of water deficit stress. The SuperSAGE libraries produced 8,787,315 tags (26 bp) that, after exclusion of singlets, allowed the identification of 205,975 unitags. Most relevant BlastN matches comprised 567,420 tags, regarding 75,404 unitags with 164,860 different ESTs. To optimize the annotation efficiency, the Gene Ontology (GO) categorization was carried out for 186,191 ESTs (BlastN against Uniprot-SwissProt), permitting the categorization of 118,208 ESTs (63.5%). In an attempt to elect a group of the best tags to be validated by RTqPCR, the GO categorization of the tag-related ESTs allowed the in silico identification of 213 upregulated unitags responding basically to abiotic stresses, from which 145 presented no hits after BlastN analysis, probably concerning new genes still uncovered in previous studies. The present report analyzes the sugarcane transcriptome under drought stress, using a combination of high-throughput transcriptome profiling by SuperSAGE with the Solexa sequencing technology, allowing the identification of potential target genes during the stress response.

VL - 2012 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22629208?dopt=Abstract ER - TY - JOUR T1 - Polimorphisms in inflammasome genes are involved in the predisposition to systemic lupus erythematosus. JF - Autoimmunity Y1 - 2012 A1 - Pontillo, Alessandra A1 - Girardelli, Martina A1 - Kamada, Anselmo J A1 - Pancotto, Joao A T A1 - Donadi, Eduardo A A1 - Crovella, Sergio A1 - Sandrin-Garcia, Paula KW - Adaptor Proteins, Signal Transducing KW - Adult KW - Alleles KW - Apoptosis Regulatory Proteins KW - Brazil KW - Female KW - Genetic Predisposition to Disease KW - Genotype KW - Haplotypes KW - Humans KW - Inflammasomes KW - Lupus Erythematosus, Systemic KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide AB -

Recent findings provide evidence of inflammasome critical role in the predisposition to autoimmune disorders. The involvement of inflammasome in the pathogenesis of systemic lupus erythematosus (SLE) has been hypothesized even if no significant association within inflammasome genes mutations or polymorphisms and lupus has been reported yet. We analyzed 14 single nucleotide polymorphisms (SNPs) within 7 inflammasome genes (NLRP1, NLRP3, NLRC4, AIM2, CARD8, CASP1, IL1B) in 144 patients affected by systemic lupus erythematosus and in 158 healthy controls from Southern Brazilian (state of São Paulo) with the aim of disclosing the possible role of inflammasome genes in the susceptibility of SLE. Our results demonstrated that NLRP1 rs2670660 SNP and the NLRP1 rs12150220-rs2670660 A-G haplotype were associated with SLE in our study population, and in particular with the development of nephritis, rash and arthritis. These findings are concordant with previously reported association of NLRP1 with vitiligo and type-1 diabetes underlining once more the involvement of NALP1 inflammasome in the pathogenesis of autoimmune disorders.

VL - 45 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22235789?dopt=Abstract ER - TY - JOUR T1 - Polymorphisms in inflammasome' genes and susceptibility to HIV-1 infection. JF - J Acquir Immune Defic Syndr Y1 - 2012 A1 - Pontillo, Alessandra A1 - Oshiro, Telma M A1 - Girardelli, Martina A1 - Kamada, Anselmo J A1 - Crovella, Sergio A1 - Duarte, Alberto J S KW - Adaptor Proteins, Signal Transducing KW - Adult KW - Apoptosis Regulatory Proteins KW - Brazil KW - Calcium-Binding Proteins KW - CARD Signaling Adaptor Proteins KW - Carrier Proteins KW - Caspase 1 KW - Female KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genotype KW - HIV Infections KW - HIV-1 KW - Humans KW - Inflammasomes KW - Interleukin-1beta KW - Intracellular Signaling Peptides and Proteins KW - Male KW - Middle Aged KW - Neoplasm Proteins KW - Polymorphism, Single Nucleotide AB -

The involvement of inflammasome genes in the susceptibility to HIV-1 infection was investigated. Twelve single nucleotide polymorphisms within NLRP1, NLRP3, NLRC4, CARD8, CASP1, and IL1B genes were analyzed in 150 HIV-1-infected Brazilian subjects and 158 healthy controls. The 2 polymorphisms rs10754558 in NLRP3 and rs1143634 in IL1B were significantly associated to the HIV-1 infection. These findings supported the previously hypothesized involvement of NALP3-inflammasome in HIV-1 pathogenesis, underlining once more the key role of inflammation and innate immunity in the susceptibility to HIV-1 infection.

VL - 59 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22227487?dopt=Abstract ER - TY - JOUR T1 - Sedation with intranasal midazolam of Angolan children undergoing invasive procedures. JF - Acta Paediatr Y1 - 2012 A1 - Kawanda, Lumana A1 - Capobianco, Ivan A1 - Starc, Meta A1 - Felipe, Daniel A1 - Zanon, Davide A1 - Barbi, Egidio A1 - Munkela, Nadine A1 - Rodrigues, Verónica A1 - Malundo, Lúis A1 - Not, Tarcisio KW - Administration, Intranasal KW - Adolescent KW - Ambulatory Surgical Procedures KW - Angola KW - Child KW - Child Behavior KW - Child, Preschool KW - Conscious Sedation KW - Crying KW - Female KW - Humans KW - Hypnotics and Sedatives KW - Infant KW - Male KW - Midazolam KW - Prospective Studies AB -

AIM: Ambulatory surgery is a daily requirement in poor countries, and limited means and insufficient trained staff lead to the lack of attention to the patient's pain. Midazolam is a rapid-onset, short-acting benzodiazepine which is used safely to reduce pain in children. We evaluated the practicability of intranasal midazolam sedation in a suburban hospital in Luanda (Angola), during the surgical procedures.

METHODS: Intranasal midazolam solution was administered at a dose of 0.5 mg/kg. Using the Ramsay's reactivity score, we gave a score to four different types of children's behaviour: moaning, shouting, crying and struggling, and the surgeon evaluated the ease of completing the surgical procedure using scores from 0 (very easy) to 3 (managing with difficulty).

RESULTS: Eighty children (median age, 3 years) were recruited, and 140 surgical procedures were performed. Fifty-two children were treated with midazolam during 85 procedures, and 28 children were not treated during 55 procedures. We found a significant difference between the two groups on the shouting, crying and struggling parameters (p < 0.001). The mean score of the ease of completing the procedures was significantly different among the two groups (p < 0.0001).

CONCLUSION: These results provide a model of procedural sedation in ambulatory surgical procedures in poor countries, thus abolishing pain and making the surgeon's job easier.

VL - 101 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22458936?dopt=Abstract ER - TY - JOUR T1 - Serum amyloid A and cholesterol: a pivotal role on inflammation. JF - Amyloid Y1 - 2012 A1 - Tricarico, Paola Maura A1 - Marcuzzi, Annalisa A1 - Zanin, Valentina A1 - Kleiner, Giulio A1 - Bianco, Anna Monica A1 - Crovella, Sergio KW - Animals KW - Humans KW - Serum Amyloid A Protein VL - 19 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22624603?dopt=Abstract ER - TY - JOUR T1 - Breastfeeding to 24 months of age in the northeast of Italy: a cohort study. JF - Breastfeed Med Y1 - 2011 A1 - Carletti, Claudia A1 - Pani, Paola A1 - Knowles, Alessandra A1 - Monasta, Lorenzo A1 - Montico, Marcella A1 - Cattaneo, Adriano KW - Adult KW - Age Factors KW - Birth Weight KW - Breast Feeding KW - Cohort Studies KW - Family Characteristics KW - Female KW - Gestational Age KW - Guideline Adherence KW - Health Promotion KW - Humans KW - Infant KW - Infant, Newborn KW - Italy KW - Neonatal Screening KW - Prevalence KW - Socioeconomic Factors KW - Time Factors AB -

AIM: This study assessed the prevalence and duration of breastfeeding up to 24 months and the associated socioeconomic determinants in a birth cohort of children.

METHODS: Four hundred infants born in a hospital in the north east of Italy were enrolled at birth and followed up for 36 months. Data on infant feeding were gathered through a feeding diary compiled at fixed intervals. Data were also gathered on type of delivery and weight, length, and health status at birth, as well as on selected socioeconomic indicators of the mothers. A multivariate logistic regression analysis was used to determine any association that exclusivity and duration of breastfeeding may have with selected socioeconomic variables and with health conditions of the infants at birth.

RESULTS: Ninety-eight percent of mothers initiated breastfeeding, 69% of them exclusively. This rate, however, had declined to 6% by 6 months. There was a remarkable endurance of breastfeeding at 24 months (12%). The variables significantly associated with exclusive breastfeeding at 3 months and any form of breastfeeding at 12 months are mother's age (p=0.007 at 3 months, p=0.026 at 12 months) and postdischarge hospital admission (p=0.029 at 3 months).

CONCLUSIONS: In this population, breastfeeding rates are higher than previously reported, but lower than recommended, especially as far as exclusivity is concerned. Full implementation of the World Health Organization-UNICEF Baby Friendly Initiatives in hospitals and communities is needed to improve them further. Monitoring systems should include the collection of data on breastfeeding beyond 12 months of age.

VL - 6 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21770733?dopt=Abstract ER - TY - JOUR T1 - Clinical heterogeneity and diagnostic delay of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome. JF - Clin Immunol Y1 - 2011 A1 - Mazza, Cinzia A1 - Buzi, Fabio A1 - Ortolani, Federica A1 - Vitali, Alberto A1 - Notarangelo, Lucia D A1 - Weber, Giovanna A1 - Bacchetta, Rosa A1 - Soresina, Annarosa A1 - Lougaris, Vassilios A1 - Greggio, Nella A A1 - Taddio, Andrea A1 - Pasic, Srdjan A1 - de Vroede, Monique A1 - Pac, Malgorzata A1 - Kilic, Sara Sebnem A1 - Ozden, Sanal A1 - Rusconi, Roberto A1 - Martino, Silvana A1 - Capalbo, Donatella A1 - Salerno, Mariacarolina A1 - Pignata, Claudio A1 - Radetti, Giorgio A1 - Maggiore, Giuseppe A1 - Plebani, Alessandro A1 - Notarangelo, Luigi D A1 - Badolato, Raffaele KW - Adolescent KW - Adult KW - Child KW - Child, Preschool KW - Heterozygote KW - Homozygote KW - Humans KW - Middle Aged KW - Mutation KW - Polyendocrinopathies, Autoimmune KW - Time Factors KW - Young Adult AB -

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive organ-specific autoimmune disorder that is characterized by a variable combination of (i) chronic mucocutaneous candidiasis, (ii) polyendocrinopathy and/or hepatitis and (iii) dystrophy of the dental enamel and nails. We analyzed the AIRE (autoimmune regulator) gene in subjects who presented any symptom that has been associated with APECED, including candidiasis and autoimmune endocrinopathy. We observed that 83.3% of patients presented at least two of the three typical manifestations of APECED, while the remaining 16.7% of patients showed other signs of the disease. Analysis of the genetic diagnosis of these subjects revealed that a considerable delay occurs in the majority of patients between the appearance of symptoms and the diagnosis. Overall, the mean diagnostic delay in our patients was 10.2 years. These results suggest that molecular analysis of AIRE should be performed in patients with relapsing mucocutaneous candidiasis for early identification of APECED.

VL - 139 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21295522?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. JF - Nat Genet Y1 - 2011 A1 - Wain, Louise V A1 - Verwoert, Germaine C A1 - O'Reilly, Paul F A1 - Shi, Gang A1 - Johnson, Toby A1 - Johnson, Andrew D A1 - Bochud, Murielle A1 - Rice, Kenneth M A1 - Henneman, Peter A1 - Smith, Albert V A1 - Ehret, Georg B A1 - Amin, Najaf A1 - Larson, Martin G A1 - Mooser, Vincent A1 - Hadley, David A1 - Dörr, Marcus A1 - Bis, Joshua C A1 - Aspelund, Thor A1 - Esko, Tõnu A1 - Janssens, A Cecile J W A1 - Zhao, Jing Hua A1 - Heath, Simon A1 - Laan, Maris A1 - Fu, Jingyuan A1 - Pistis, Giorgio A1 - Luan, Jian'an A1 - Arora, Pankaj A1 - Lucas, Gavin A1 - Pirastu, Nicola A1 - Pichler, Irene A1 - Jackson, Anne U A1 - Webster, Rebecca J A1 - Zhang, Feng A1 - Peden, John F A1 - Schmidt, Helena A1 - Tanaka, Toshiko A1 - Campbell, Harry A1 - Igl, Wilmar A1 - Milaneschi, Yuri A1 - Hottenga, Jouke-Jan A1 - Vitart, Veronique A1 - Chasman, Daniel I A1 - Trompet, Stella A1 - Bragg-Gresham, Jennifer L A1 - Alizadeh, Behrooz Z A1 - Chambers, John C A1 - Guo, Xiuqing A1 - Lehtimäki, Terho A1 - Kuhnel, Brigitte A1 - Lopez, Lorna M A1 - Polasek, Ozren A1 - Boban, Mladen A1 - Nelson, Christopher P A1 - Morrison, Alanna C A1 - Pihur, Vasyl A1 - Ganesh, Santhi K A1 - Hofman, Albert A1 - Kundu, Suman A1 - Mattace-Raso, Francesco U S A1 - Rivadeneira, Fernando A1 - Sijbrands, Eric J G A1 - Uitterlinden, André G A1 - Hwang, Shih-Jen A1 - Vasan, Ramachandran S A1 - Wang, Thomas J A1 - Bergmann, Sven A1 - Vollenweider, Peter A1 - Waeber, Gerard A1 - Laitinen, Jaana A1 - Pouta, Anneli A1 - Zitting, Paavo A1 - McArdle, Wendy L A1 - Kroemer, Heyo K A1 - Völker, Uwe A1 - Völzke, Henry A1 - Glazer, Nicole L A1 - Taylor, Kent D A1 - Harris, Tamara B A1 - Alavere, Helene A1 - Haller, Toomas A1 - Keis, Aime A1 - Tammesoo, Mari-Liis A1 - Aulchenko, Yurii A1 - Barroso, Inês A1 - Khaw, Kay-Tee A1 - Galan, Pilar A1 - Hercberg, Serge A1 - Lathrop, Mark A1 - Eyheramendy, Susana A1 - Org, Elin A1 - Sõber, Siim A1 - Lu, Xiaowen A1 - Nolte, Ilja M A1 - Penninx, Brenda W A1 - Corre, Tanguy A1 - Masciullo, Corrado A1 - Sala, Cinzia A1 - Groop, Leif A1 - Voight, Benjamin F A1 - Melander, Olle A1 - O'Donnell, Christopher J A1 - Salomaa, Veikko A1 - d'Adamo, Adamo Pio A1 - Fabretto, Antonella A1 - Faletra, Flavio A1 - Ulivi, Sheila A1 - Del Greco, Fabiola M A1 - Facheris, Maurizio A1 - Collins, Francis S A1 - Bergman, Richard N A1 - Beilby, John P A1 - Hung, Joseph A1 - Musk, A William A1 - Mangino, Massimo A1 - Shin, So-Youn A1 - Soranzo, Nicole A1 - Watkins, Hugh A1 - Goel, Anuj A1 - Hamsten, Anders A1 - Gider, Pierre A1 - Loitfelder, Marisa A1 - Zeginigg, Marion A1 - Hernandez, Dena A1 - Najjar, Samer S A1 - Navarro, Pau A1 - Wild, Sarah H A1 - Corsi, Anna Maria A1 - Singleton, Andrew A1 - de Geus, Eco J C A1 - Willemsen, Gonneke A1 - Parker, Alex N A1 - Rose, Lynda M A1 - Buckley, Brendan A1 - Stott, David A1 - Orru, Marco A1 - Uda, Manuela A1 - van der Klauw, Melanie M A1 - Zhang, Weihua A1 - Li, Xinzhong A1 - Scott, James A1 - Chen, Yii-Der Ida A1 - Burke, Gregory L A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Döring, Angela A1 - Meitinger, Thomas A1 - Davies, Gail A1 - Starr, John M A1 - Emilsson, Valur A1 - Plump, Andrew A1 - Lindeman, Jan H A1 - Hoen, Peter A C 't A1 - König, Inke R A1 - Felix, Janine F A1 - Clarke, Robert A1 - Hopewell, Jemma C A1 - Ongen, Halit A1 - Breteler, Monique A1 - Debette, Stéphanie A1 - Destefano, Anita L A1 - Fornage, Myriam A1 - Mitchell, Gary F A1 - Smith, Nicholas L A1 - Holm, Hilma A1 - Stefansson, Kari A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Samani, Nilesh J A1 - Preuss, Michael A1 - Rudan, Igor A1 - Hayward, Caroline A1 - Deary, Ian J A1 - Wichmann, H-Erich A1 - Raitakari, Olli T A1 - Palmas, Walter A1 - Kooner, Jaspal S A1 - Stolk, Ronald P A1 - Jukema, J Wouter A1 - Wright, Alan F A1 - Boomsma, Dorret I A1 - Bandinelli, Stefania A1 - Gyllensten, Ulf B A1 - Wilson, James F A1 - Ferrucci, Luigi A1 - Schmidt, Reinhold A1 - Farrall, Martin A1 - Spector, Tim D A1 - Palmer, Lyle J A1 - Tuomilehto, Jaakko A1 - Pfeufer, Arne A1 - Gasparini, Paolo A1 - Siscovick, David A1 - Altshuler, David A1 - Loos, Ruth J F A1 - Toniolo, Daniela A1 - Snieder, Harold A1 - Gieger, Christian A1 - Meneton, Pierre A1 - Wareham, Nicholas J A1 - Oostra, Ben A A1 - Metspalu, Andres A1 - Launer, Lenore A1 - Rettig, Rainer A1 - Strachan, David P A1 - Beckmann, Jacques S A1 - Witteman, Jacqueline C M A1 - Erdmann, Jeanette A1 - van Dijk, Ko Willems A1 - Boerwinkle, Eric A1 - Boehnke, Michael A1 - Ridker, Paul M A1 - Järvelin, Marjo-Riitta A1 - Chakravarti, Aravinda A1 - Abecasis, Goncalo R A1 - Gudnason, Vilmundur A1 - Newton-Cheh, Christopher A1 - Levy, Daniel A1 - Munroe, Patricia B A1 - Psaty, Bruce M A1 - Caulfield, Mark J A1 - Rao, Dabeeru C A1 - Tobin, Martin D A1 - Elliott, Paul A1 - van Duijn, Cornelia M KW - Arteries KW - Blood Pressure KW - Case-Control Studies KW - Follow-Up Studies KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Linkage Disequilibrium KW - Polymorphism, Single Nucleotide AB -

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.

VL - 43 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21909110?dopt=Abstract ER - TY - JOUR T1 - High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study. JF - Arthritis Rheum Y1 - 2011 A1 - Tanaka, Naoko A1 - Izawa, Kazushi A1 - Saito, Megumu K A1 - Sakuma, Mio A1 - Oshima, Koichi A1 - Ohara, Osamu A1 - Nishikomori, Ryuta A1 - Morimoto, Takeshi A1 - Kambe, Naotomo A1 - Goldbach-Mansky, Raphaela A1 - Aksentijevich, Ivona A1 - de Saint Basile, Geneviève A1 - Neven, Bénédicte A1 - van Gijn, Mariëlle A1 - Frenkel, Joost A1 - Aróstegui, Juan I A1 - Yagüe, Jordi A1 - Merino, Rosa A1 - Ibañez, Mercedes A1 - Pontillo, Alessandra A1 - Takada, Hidetoshi A1 - Imagawa, Tomoyuki A1 - Kawai, Tomoki A1 - Yasumi, Takahiro A1 - Nakahata, Tatsutoshi A1 - Heike, Toshio KW - Adolescent KW - Adult KW - Carrier Proteins KW - Case-Control Studies KW - Child KW - Child, Preschool KW - Cryopyrin-Associated Periodic Syndromes KW - Female KW - Genetic Association Studies KW - Humans KW - Infant KW - Male KW - Mosaicism AB -

OBJECTIVE: Chronic infantile neurologic, cutaneous, articular (CINCA) syndrome, also known as neonatal-onset multisystem inflammatory disease (NOMID), is a dominantly inherited systemic autoinflammatory disease. Although heterozygous germline gain-of-function NLRP3 mutations are a known cause of this disease, conventional genetic analyses fail to detect disease-causing mutations in ∼40% of patients. Since somatic NLRP3 mosaicism has been detected in several mutation-negative NOMID/CINCA syndrome patients, we undertook this study to determine the precise contribution of somatic NLRP3 mosaicism to the etiology of NOMID/CINCA syndrome.

METHODS: An international case-control study was performed to detect somatic NLRP3 mosaicism in NOMID/CINCA syndrome patients who had shown no mutation during conventional sequencing. Subcloning and sequencing of NLRP3 was performed in these mutation-negative NOMID/CINCA syndrome patients and their healthy relatives. Clinical features were analyzed to identify potential genotype-phenotype associations.

RESULTS: Somatic NLRP3 mosaicism was identified in 18 of the 26 patients (69.2%). Estimates of the level of mosaicism ranged from 4.2% to 35.8% (mean ± SD 12.1 ± 7.9%). Mosaicism was not detected in any of the 19 healthy relatives (18 of 26 patients versus 0 of 19 relatives; P < 0.0001). In vitro functional assays indicated that the detected somatic NLRP3 mutations had disease-causing functional effects. No differences in NLRP3 mosaicism were detected between different cell lineages. Among nondescript clinical features, a lower incidence of mental retardation was noted in patients with somatic mosaicism. Genotype-matched comparison confirmed that patients with somatic NLRP3 mosaicism presented with milder neurologic symptoms.

CONCLUSION: Somatic NLRP3 mutations were identified in 69.2% of patients with mutation-negative NOMID/CINCA syndrome. This indicates that somatic NLRP3 mosaicism is a major cause of NOMID/CINCA syndrome.

VL - 63 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21702021?dopt=Abstract ER - TY - JOUR T1 - Marriage and parenthood among childhood cancer survivors: a report from the Italian AIEOP Off-Therapy Registry. JF - Haematologica Y1 - 2011 A1 - Pivetta, Emanuele A1 - Maule, Milena M A1 - Pisani, Paola A1 - Zugna, Daniela A1 - Haupt, Riccardo A1 - Jankovic, Momcilo A1 - Aricò, Maurizio A1 - Casale, Fiorina A1 - Clerico, Anna A1 - Cordero di Montezemolo, Luca A1 - Kiren, Valentina A1 - Locatelli, Franco A1 - Palumbo, Giovanna A1 - Pession, Andrea A1 - Pillon, Marta A1 - Santoro, Nicola A1 - Terenziani, Monica A1 - Valsecchi, Maria Grazia A1 - Dama, Elisa A1 - Magnani, Corrado A1 - Merletti, Franco A1 - Pastore, Guido KW - Adult KW - Child KW - Child, Preschool KW - Cohort Studies KW - Female KW - Follow-Up Studies KW - Hematologic Neoplasms KW - Humans KW - Infant KW - Infant, Newborn KW - Italy KW - Male KW - Marriage KW - Middle Aged KW - Parents KW - Registries KW - Survivors AB -

BACKGROUND: The aim of this study was to describe the patterns of marriage and parenthood in a cohort of childhood cancer survivors included in the Off-Therapy Registry maintained by the Italian Association of Pediatric Hematology and Oncology.

DESIGN AND METHODS: We analyzed a cohort of 6,044 patients diagnosed with cancer between 1960 and 1998, while aged 0 to 14 years and who were 18 years old or older by December 2003. They were followed up through the regional vital statistics registers until death or the end of follow up (October 30, 2006), whichever occurred first, and their marital status and date of birth of their children were recorded. The cumulative probabilities of being married and having a first child were computed by gender and compared by tumor type within the cohort. Marriage and fertility rates (the latter defined as the number of live births per woman-year) were compared with those of the Italian population of the same age, gender, area of residence and calendar period by means of the observed to expected (O/E) ratios.

RESULTS: During the follow-up period, 4,633 (77%) subjects had not married. The marriage O/E ratios were 0.56 (95% CI: 0.51-0.61) and 0.70 (95% CI: 0.65-0.76) among men and women, respectively. Overall, 263 men had 367 liveborn children, and 473 women had 697 liveborn children. The female fertility O/E ratio was 0.57 (95% CI: 0.53-0.62) overall, and 1.08 (95% CI: 0.99-1.17) when analyses were restricted to married/cohabiting women

CONCLUSIONS: Childhood cancer survivors are less likely to marry and to have children than the general population, confirming the life-long impact of their previous disease on their social behavior and choices. The inclusion of counseling in the strategies of management and long-term surveillance of childhood cancer patients could be beneficial to survivors as they approach adulthood.

VL - 96 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21228031?dopt=Abstract ER - TY - JOUR T1 - Multiple loci are associated with white blood cell phenotypes. JF - PLoS Genet Y1 - 2011 A1 - Nalls, Michael A A1 - Couper, David J A1 - Tanaka, Toshiko A1 - van Rooij, Frank J A A1 - Chen, Ming-Huei A1 - Smith, Albert V A1 - Toniolo, Daniela A1 - Zakai, Neil A A1 - Yang, Qiong A1 - Greinacher, Andreas A1 - Wood, Andrew R A1 - Garcia, Melissa A1 - Gasparini, Paolo A1 - Liu, Yongmei A1 - Lumley, Thomas A1 - Folsom, Aaron R A1 - Reiner, Alex P A1 - Gieger, Christian A1 - Lagou, Vasiliki A1 - Felix, Janine F A1 - Völzke, Henry A1 - Gouskova, Natalia A A1 - Biffi, Alessandro A1 - Döring, Angela A1 - Völker, Uwe A1 - Chong, Sean A1 - Wiggins, Kerri L A1 - Rendon, Augusto A1 - Dehghan, Abbas A1 - Moore, Matt A1 - Taylor, Kent A1 - Wilson, James G A1 - Lettre, Guillaume A1 - Hofman, Albert A1 - Bis, Joshua C A1 - Pirastu, Nicola A1 - Fox, Caroline S A1 - Meisinger, Christa A1 - Sambrook, Jennifer A1 - Arepalli, Sampath A1 - Nauck, Matthias A1 - Prokisch, Holger A1 - Stephens, Jonathan A1 - Glazer, Nicole L A1 - Cupples, L Adrienne A1 - Okada, Yukinori A1 - Takahashi, Atsushi A1 - Kamatani, Yoichiro A1 - Matsuda, Koichi A1 - Tsunoda, Tatsuhiko A1 - Tanaka, Toshihiro A1 - Kubo, Michiaki A1 - Nakamura, Yusuke A1 - Yamamoto, Kazuhiko A1 - Kamatani, Naoyuki A1 - Stumvoll, Michael A1 - Tönjes, Anke A1 - Prokopenko, Inga A1 - Illig, Thomas A1 - Patel, Kushang V A1 - Garner, Stephen F A1 - Kuhnel, Brigitte A1 - Mangino, Massimo A1 - Oostra, Ben A A1 - Thein, Swee Lay A1 - Coresh, Josef A1 - Wichmann, H-Erich A1 - Menzel, Stephan A1 - Lin, JingPing A1 - Pistis, Giorgio A1 - Uitterlinden, André G A1 - Spector, Tim D A1 - Teumer, Alexander A1 - Eiriksdottir, Gudny A1 - Gudnason, Vilmundur A1 - Bandinelli, Stefania A1 - Frayling, Timothy M A1 - Chakravarti, Aravinda A1 - van Duijn, Cornelia M A1 - Melzer, David A1 - Ouwehand, Willem H A1 - Levy, Daniel A1 - Boerwinkle, Eric A1 - Singleton, Andrew B A1 - Hernandez, Dena G A1 - Longo, Dan L A1 - Soranzo, Nicole A1 - Witteman, Jacqueline C M A1 - Psaty, Bruce M A1 - Ferrucci, Luigi A1 - Harris, Tamara B A1 - O'Donnell, Christopher J A1 - Ganesh, Santhi K KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Leukocyte Count KW - Leukocytes KW - Molecular Epidemiology KW - Multigene Family KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Ubiquitin-Protein Ligases AB -

White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count- 3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.

VL - 7 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21738480?dopt=Abstract ER - TY - JOUR T1 - Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families. JF - Blood Y1 - 2011 A1 - Noris, Patrizia A1 - Perrotta, Silverio A1 - Seri, Marco A1 - Pecci, Alessandro A1 - Gnan, Chiara A1 - Loffredo, Giuseppe A1 - Pujol-Moix, Núria A1 - Zecca, Marco A1 - Scognamiglio, Francesca A1 - De Rocco, Daniela A1 - Punzo, Francesca A1 - Melazzini, Federica A1 - Scianguetta, Saverio A1 - Casale, Maddalena A1 - Marconi, Caterina A1 - Pippucci, Tommaso A1 - Amendola, Giovanni A1 - Notarangelo, Lucia D A1 - Klersy, Catherine A1 - Civaschi, Elisa A1 - Balduini, Carlo L A1 - Savoia, Anna KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Ankyrin Repeat KW - Child KW - Cohort Studies KW - Family KW - Female KW - Gene Frequency KW - Humans KW - Inheritance Patterns KW - Male KW - Middle Aged KW - Mutation KW - Pedigree KW - Thrombocytopenia KW - Transcription Factors KW - Young Adult AB -

Until recently, thrombocytopenia 2 (THC2) was considered an exceedingly rare form of autosomal dominant thrombocytopenia and only 2 families were known. However, we recently identified mutations in the 5'-untranslated region of the ANKRD26 gene in 9 THC2 families. Here we report on 12 additional pedigrees with ANKRD26 mutations, 6 of which are new. Because THC2 affected 21 of the 210 families in our database, it has to be considered one of the less rare forms of inherited thrombocytopenia. Analysis of all 21 families with ANKRD26 mutations identified to date revealed that thrombocytopenia and bleeding tendency were usually mild. Nearly all patients had no platelet macrocytosis, and this characteristic distinguishes THC2 from most other forms of inherited thrombocytopenia. In the majority of cases, platelets were deficient in glycoprotein Ia and α-granules, whereas in vitro platelet aggregation was normal. Bone marrow examination and serum thrombopoietin levels suggested that thrombocytopenia was derived from dysmegakaryopoiesis. Unexplained high values of hemoglobin and leukocytes were observed in a few cases. An unexpected finding that warrants further investigation was a high incidence of acute leukemia. Given the scarcity of distinctive characteristics, the ANKRD26-related thrombocytopenia has to be taken into consideration in the differential diagnosis of isolated thrombocytopenias.

VL - 117 IS - 24 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21467542?dopt=Abstract ER - TY - JOUR T1 - Osteoprotegerin promotes vascular fibrosis via a TGF-β1 autocrine loop. JF - Atherosclerosis Y1 - 2011 A1 - Toffoli, Barbara A1 - Pickering, Raelene J A1 - Tsorotes, Despina A1 - Wang, Bo A1 - Bernardi, Stella A1 - Kantharidis, Phillip A1 - Fabris, Bruno A1 - Zauli, Giorgio A1 - Secchiero, Paola A1 - Thomas, Merlin C KW - Animals KW - Apolipoproteins E KW - Cell Proliferation KW - Collagen KW - Fibronectins KW - Fibrosis KW - Gene Expression Regulation KW - Humans KW - Mice KW - Mice, Inbred C57BL KW - Mice, Transgenic KW - Muscle, Smooth, Vascular KW - Myocytes, Smooth Muscle KW - Osteoprotegerin KW - Platelet-Derived Growth Factor KW - Transforming Growth Factor beta1 AB -

BACKGROUND: This study was designed to evaluate the potential role of osteoprotegerin (OPG) in arterial fibrosis.

METHODS: Aortic samples were analyzed after in vivo treatment of ApoE(-/-) mice with recombinant human OPG. Mouse vascular smooth muscle cells (VSMC) were exposed in vitro to recombinant OPG and analyzed for markers of inflammation and fibrosis, such as fibronectin, collagen I, III, IV and transforming growth factor-β1 (TGF-β1). Conversely, the potential modulation of endogenous OPG expression and release by VSMC was analyzed in response to different pro-atherosclerotic cytokines, TGF-β1, platelet derived growth factor (PDGF) and angiogensin II (Ang II).

RESULTS: In vivo treatment with human OPG induced signs of fibrosis and up-regulated the arterial expression of TGF-β1. Consistently, in vitro treatment of VSMC with human OPG induced the expression of fibronectin, collagen type I, III, IV, metalloprotein-2 (MMP-2) and MMP-9, as well as of TGF-β1. On the other hand, exposure to recombinant TGF-β1 promoted the expression/release of endogenous OPG and mediated the increase of OPG release induced by PDGF and Ang II in VSMC.

CONCLUSIONS: Taken together, these data support a pathogenic role for OPG in the development and progression of atherosclerotic lesions and suggest the existence of a vicious circle between TGF-β1 and OPG.

VL - 218 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21679949?dopt=Abstract ER - TY - JOUR T1 - Phospholipase C-β3 is a key modulator of IL-8 expression in cystic fibrosis bronchial epithelial cells. JF - J Immunol Y1 - 2011 A1 - Bezzerri, Valentino A1 - d'Adamo, Pio A1 - Rimessi, Alessandro A1 - Lanzara, Carmen A1 - Crovella, Sergio A1 - Nicolis, Elena A1 - Tamanini, Anna A1 - Athanasakis, Emmanouil A1 - Tebon, Maela A1 - Bisoffi, Giulia A1 - Drumm, Mitchell L A1 - Knowles, Michael R A1 - Pinton, Paolo A1 - Gasparini, Paolo A1 - Berton, Giorgio A1 - Cabrini, Giulio KW - Adenosine Triphosphate KW - Calcium KW - Cell Line, Transformed KW - Cystic Fibrosis KW - Enzyme Activation KW - Epithelial Cells KW - Gene Expression KW - Gene Frequency KW - Genotype KW - Green Fluorescent Proteins KW - Host-Pathogen Interactions KW - Humans KW - Interleukin-8 KW - Isoenzymes KW - Lung Diseases KW - Microscopy, Fluorescence KW - Phospholipase C beta KW - Polymorphism, Single Nucleotide KW - Protein Kinase C KW - Protein Kinase C beta KW - Pseudomonas aeruginosa KW - RNA Interference KW - Toll-Like Receptors KW - Transcription Factor RelA AB -

Respiratory insufficiency is the major cause of morbidity and mortality in patients affected by cystic fibrosis (CF). An excessive neutrophilic inflammation, mainly orchestrated by the release of IL-8 from bronchial epithelial cells and amplified by chronic bacterial infection with Pseudomonas aeruginosa, leads to progressive tissue destruction. The anti-inflammatory drugs presently used in CF patients have several limitations, indicating the need for identifying novel molecular targets. To address this issue, we preliminarily studied the association of 721 single nucleotide polymorphisms from 135 genes potentially involved in signal transduction implicated in neutrophil recruitment in a cohort of F508del homozygous CF patients with either severe or mild progression of lung disease. The top ranking association was found for a nonsynonymous polymorphism of the phospholipase C-β3 (PLCB3) gene. Studies in bronchial epithelial cells exposed to P. aeruginosa revealed that PLCB3 is implicated in extracellular nucleotide-dependent intracellular calcium signaling, leading to activation of the protein kinase Cα and Cβ and of the nuclear transcription factor NF-κB p65. The proinflammatory pathway regulated by PLCB3 acts by potentiating the Toll-like Receptors' signaling cascade and represents an interesting molecular target to attenuate the excessive recruitment of neutrophils without completely abolishing the inflammatory response.

VL - 186 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21411730?dopt=Abstract ER - TY - JOUR T1 - The role of mannose-binding lectin gene polymorphisms in susceptibility to HIV-1 infection in Southern Brazilian patients. JF - AIDS Y1 - 2011 A1 - da Silva, Gabriela Kniphoff A1 - Guimarães, Rafael A1 - Mattevi, Vanessa Suñé A1 - Lazzaretti, Rosmeri Kuhmmer A1 - Sprinz, Eduardo A1 - Kuhmmer, Regina A1 - Brandão, Lucas A1 - Crovella, Sergio A1 - Chies, José Artur Bogo KW - Adult KW - Aged KW - Brazil KW - Female KW - Genetic Predisposition to Disease KW - HIV Infections KW - HIV-1 KW - Humans KW - Lectins, C-Type KW - Male KW - Mannose-Binding Lectin KW - Mannose-Binding Lectins KW - Middle Aged KW - Polymorphism, Genetic KW - Promoter Regions, Genetic KW - Receptors, Cell Surface KW - Young Adult AB -

OBJECTIVE: This study investigates the role of mannose-binding lectin (MBL) in the susceptibility to HIV-1 infection analyzing polymorphisms located at the MBL2 promoter and exon 1 regions.

MATERIALS AND METHODS: The prevalence of MBL2 variant alleles was investigated in 410 HIV-1-infected patients from the South Brazilian HIV cohort and in 345 unexposed uninfected healthy individuals. The promoter variants were genotyped using polymerase chain reaction with sequence-specific primers (PCR-SSP) and exon 1 variants were analyzed by real-time PCR using a melting temperature assay and were confirmed by PCR-restriction fragment length polymorphism (RFLP). MBL2 genotypic and allelic frequencies were compared between HIV-1-infected patients and controls using the chi-squared tests.

RESULTS: The analyses were performed subdividing the individuals according to their ethnic origin. Among Euro-derived individuals a higher frequency of the LX/LX genotype was observed in patients when compared to controls (P < 0.001). The haplotypic analysis also showed a higher frequency of the haplotypes associated with lower MBL levels among HIV-1-infected patients (P = 0.0001). Among Afro-derived individuals the frequencies of LY/LY and HY/HY genotypes were higher in patients when compared to controls (P = 0.009 and P = 0.02).

CONCLUSIONS: An increased frequency of MBL2 genotypes associated with low MBL levels was observed in Euro-derived patients, suggesting a potential role for MBL in the susceptibility to HIV-1 infection in Euro-derived individuals.

VL - 25 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21192229?dopt=Abstract ER - TY - JOUR T1 - A singular case of congenital self-healing histiocytosis with skin, liver and atypical eye involvement. JF - Ocul Immunol Inflamm Y1 - 2011 A1 - Parentin, Fulvio A1 - Ventura, Giovanna A1 - Pastore, Serena A1 - Kiren, Valentina A1 - Bibalo, Chiara A1 - Pensiero, Stefano A1 - Lepore, Loredana KW - Antigens, CD1 KW - Convalescence KW - Female KW - Glaucoma KW - Histiocytosis, Langerhans-Cell KW - Humans KW - Infant KW - Intraocular Pressure KW - Iridocorneal Endothelial Syndrome KW - Liver Diseases KW - S100 Proteins KW - Skin Diseases KW - Trabeculectomy AB -

PURPOSE: To describe a rare case of congenital self-healing Langerhans cell histiocytosis (CSHLCH) presenting with atypical eye involvement.

DESIGN: Case report.

METHODS: A female newborn presented with purpuric lesions over the trunk, limbs, and face. Liver ultrasonography revealed hypoechogenic lesions with blurred borders. Biomicroscopy showed right posterior synechiae with fibrinoid deposits on the lens. At 7 months she presented with right acute glaucoma.

RESULTS: Biomicroscopy showed the presence of inflammatory pseudo-membrane covering the anterior surface of the lens, iris, and iridocorneal angle. Ab externo trabeculotomy was performed; access to the anterior chamber with capsulorrhexis forceps permitted a peeling of the pseudo-membrane with normalization of the intraocular pressure. Histologic examination of the membrane revealed an inflammatory tissue with CD1a and S-100 positive histiocytic cells.

CONCLUSIONS: This is the first case of CSHLCH describing acute glaucoma secondary to a pseudo-inflammatory membrane with typical histiocytic cells, occluding the iridocorneal angle.

VL - 19 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21864117?dopt=Abstract ER - TY - JOUR T1 - Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. JF - Nat Genet Y1 - 2011 A1 - Pansuriya, Twinkal C A1 - van Eijk, Ronald A1 - d'Adamo, Pio A1 - van Ruler, Maayke A J H A1 - Kuijjer, Marieke L A1 - Oosting, Jan A1 - Cleton-Jansen, Anne-Marie A1 - van Oosterwijk, Jolieke G A1 - Verbeke, Sofie L J A1 - Meijer, Daniëlle A1 - van Wezel, Tom A1 - Nord, Karolin H A1 - Sangiorgi, Luca A1 - Toker, Berkin A1 - Liegl-Atzwanger, Bernadette A1 - San-Julian, Mikel A1 - Sciot, Raf A1 - Limaye, Nisha A1 - Kindblom, Lars-Gunnar A1 - Daugaard, Soeren A1 - Godfraind, Catherine A1 - Boon, Laurence M A1 - Vikkula, Miikka A1 - Kurek, Kyle C A1 - Szuhai, Karoly A1 - French, Pim J A1 - Bovée, Judith V M G KW - Adult KW - Case-Control Studies KW - Cell Line, Tumor KW - DNA Methylation KW - Enchondromatosis KW - Female KW - Gene Expression Profiling KW - Gene Expression Regulation KW - Genome-Wide Association Study KW - Humans KW - Isocitrate Dehydrogenase KW - Male KW - Middle Aged KW - Mosaicism KW - Mutation, Missense KW - Sequence Analysis, DNA KW - Transcription, Genetic KW - Young Adult AB -

Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). We report somatic heterozygous mutations in IDH1 (c.394C>T encoding an R132C substitution and c.395G>A encoding an R132H substitution) or IDH2 (c.516G>C encoding R172S) in 87% of enchondromas (benign cartilage tumors) and in 70% of spindle cell hemangiomas (benign vascular lesions). In total, 35 of 43 (81%) subjects with Ollier disease and 10 of 13 (77%) with Maffucci syndrome carried IDH1 (98%) or IDH2 (2%) mutations in their tumors. Fourteen of 16 subjects had identical mutations in separate lesions. Immunohistochemistry to detect mutant IDH1 R132H protein suggested intraneoplastic and somatic mosaicism. IDH1 mutations in cartilage tumors were associated with hypermethylation and downregulated expression of several genes. Mutations were also found in 40% of solitary central cartilaginous tumors and in four chondrosarcoma cell lines, which will enable functional studies to assess the role of IDH1 and IDH2 mutations in tumor formation.

VL - 43 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22057234?dopt=Abstract ER - TY - JOUR T1 - Therapeutic approaches in the treatment of juvenile dermatomyositis in patients with recent-onset disease and in those experiencing disease flare: an international multicenter PRINTO study. JF - Arthritis Rheum Y1 - 2011 A1 - Hasija, Rachana A1 - Pistorio, Angela A1 - Ravelli, Angelo A1 - Demirkaya, Erkan A1 - Khubchandani, Raju A1 - Guseinova, Dinara A1 - Malattia, Clara A1 - Canhao, Helena A1 - Harel, Liora A1 - Foell, Dirk A1 - Wouters, Carine A1 - De Cunto, Carmen A1 - Huemer, Christian A1 - Kimura, Yukiko A1 - Mangge, Harald A1 - Minetti, Carlo A1 - Nordal, Ellen Berit A1 - Philippet, Pierre A1 - Garozzo, Rosaria A1 - Martini, Alberto A1 - Ruperto, Nicolino KW - Adolescent KW - Adrenal Cortex Hormones KW - Child KW - Dermatologic Agents KW - Dermatomyositis KW - Female KW - Humans KW - Longitudinal Studies KW - Male KW - Methotrexate KW - Prospective Studies KW - Treatment Outcome AB -

OBJECTIVE: To evaluate response to therapy over a 24-month period in a large prospective international cohort of patients with juvenile dermatomyositis (DM).

METHODS: The study included 145 patients with recent-onset juvenile DM and 130 juvenile DM patients experiencing disease flare, all of whom were <18 years old. Disease activity parameters and therapeutic approaches in 4 geographic areas were analyzed at baseline and at 6, 12, and 24 months. Response was assessed according to the Pediatric Rheumatology International Trials Organization (PRINTO) juvenile DM response criteria, and data were reported "as observed" and in the intent-to-treat (ITT) population.

RESULTS: Patients with recent-onset juvenile DM at baseline had higher baseline disease activity and greater improvement over 24 months when compared to juvenile DM patients experiencing disease flare at baseline. Methotrexate (MTX) or high-dose corticosteroids were administered more frequently to patients with recent-onset juvenile DM, compared to juvenile DM patients experiencing disease flare, who were more likely to receive cyclosporine. Compared to patients from Western and Eastern Europe, a higher proportion of patients from South and Central America and North America received pulse steroids, and the average steroid dosage was higher in the North American and South and Central American patients. The use of MTX was similar in all 4 regions, while cyclosporin A was more frequently used in Western Europe. In the "as observed" analysis, 57.9% of the patients with recent-onset juvenile DM and 36.4% of the patients experiencing disease flare (P<0.001) reached at least a 70% response by PRINTO criteria at 6 months; these proportions had increased at month 24 to 78.4% and 51.2%, respectively (P<0.001). Corresponding results of the ITT analysis were much lower, with only one-third of the patients able to maintain the initial assigned therapy over 24 months.

CONCLUSION: Patients with recent-onset juvenile DM are more likely to achieve significant clinical improvement over 24 months, when compared to patients experiencing flares of juvenile DM. Internationally, various therapeutic approaches are used to treat this disease.

VL - 63 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21647864?dopt=Abstract ER - TY - JOUR T1 - X-ray fluorescence elemental mapping and microscopy to follow hepatic disposition of a Gd-based magnetic resonance imaging contrast agent. JF - Clin Exp Pharmacol Physiol Y1 - 2011 A1 - Delfino, Riccarda A1 - Altissimo, Matteo A1 - Menk, Ralf Hendrik A1 - Alberti, Roberto A1 - Klatka, Tomasz A1 - Frizzi, Tommaso A1 - Longoni, Antonio A1 - Salomè, Murielle A1 - Tromba, Giuliana A1 - Arfelli, Fulvia A1 - Clai, Milan A1 - Vaccari, Lisa A1 - Lorusso, Vito A1 - Tiribelli, Claudio A1 - Pascolo, Lorella KW - Animals KW - Contrast Media KW - Fatty Liver KW - Female KW - Gadolinium KW - Hepatitis KW - Iron KW - Liver KW - Magnetic Resonance Imaging KW - Mice KW - Mice, Inbred CBA KW - Organometallic Compounds KW - Spectrometry, X-Ray Emission AB -

1. Spatially resolved X-ray fluorescence (XRF) spectroscopy with synchrotron radiation is a technique that allows imaging and quantification of chemical elements in biological specimens with high sensitivity. In the present study, we applied XRF techniques at a macro and micro level to carry out drug distribution studies on ex vivo models to confirm the hepatobiliary disposition of the Gd-based magnetic resonance imaging contrast agent B22956/1. 2. Gd presence was selectively quantified allowing the determination of the time dependent disappearance of the drug from blood and its hepatic accumulation in mice after administration. Elemental mapping highlighted the drug distribution differences between healthy and diseased livers. XRF microanalyses showed that in CCl(4) -induced hepatitis, B22956/1 has greatly reduced hepatic accumulation, shown as a 20-fold reduction of Gd presence. Furthermore, a significant increase of Fe presence was found in steatotic compared with healthy livers, in line with the disease features. 3. The present results show that XRF might be useful in preclinical pharmacological studies with drugs containing exogenous elements. Furthermore, quantitative and high-sensitivity elemental mapping allows simultaneous detection of chemical variation, showing pathological conditions. This approach was useful in suggesting reduced B22956/1 accumulation in steatotic livers, thus opening possible new diagnostic perspectives for this drug.

VL - 38 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21957877?dopt=Abstract ER - TY - JOUR T1 - Eltrombopag for the treatment of the inherited thrombocytopenia deriving from MYH9 mutations. JF - Blood Y1 - 2010 A1 - Pecci, Alessandro A1 - Gresele, Paolo A1 - Klersy, Catherine A1 - Savoia, Anna A1 - Noris, Patrizia A1 - Fierro, Tiziana A1 - Bozzi, Valeria A1 - Mezzasoma, Anna Maria A1 - Melazzini, Federica A1 - Balduini, Carlo L KW - Administration, Oral KW - Adolescent KW - Adult KW - Benzoates KW - Dose-Response Relationship, Drug KW - Female KW - Genetic Predisposition to Disease KW - Humans KW - Hydrazines KW - Male KW - Molecular Motor Proteins KW - Mutation KW - Myosin Heavy Chains KW - Platelet Aggregation KW - Platelet Count KW - Pyrazoles KW - Receptors, Thrombopoietin KW - Survival Rate KW - Thrombocytopenia KW - Treatment Outcome KW - Young Adult AB -

Platelet transfusion is currently the primary medical treatment for reducing thrombocytopenia in patients with inherited thrombocytopenias. To evaluate whether stimulating megakaryopoiesis could increase platelet count in these conditions, we treated patients with a severe thrombocytopenia induced by MYH9 mutations (MYH9-related disease) with a nonpeptide thrombopoietin receptor agonist, eltrombopag. Twelve adult patients with MYH9-RD and platelet counts of less than 50 × 10(9)/L received 50 mg of eltrombopag orally per day for 3 weeks. Patients who achieved a platelet count higher than 150 × 10(9)/L stopped therapy, those with 100 to 150 platelets × 10(9)/L continued treatment at the same eltrombopag dose for 3 additional weeks, while those with less than 100 platelets × 10(9)/L increased the eltrombopag dose to 75 mg for 3 weeks. Major responses (platelet count of at least 100 × 10(9)/L or 3 times the baseline value) were obtained in 8 patients, minor responses (platelet counts at least twice the baseline value) in 3. One patient did not respond. Bleeding tendency disappeared in 8 of 10 patients with bleeding symptoms at baseline. Mild adverse events were reported in 2 patients. The availability of thrombopoietin mimetics opened new prospects in the treatment of inherited thrombocytopenias. This study is registered at www.clinicaltrials.gov as NCT01133860 (European Union Drug Regulating Authorities Clinical Trials number 2008-001903-42).

VL - 116 IS - 26 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20844233?dopt=Abstract ER - TY - JOUR T1 - EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part I: Overall methodology and clinical characterisation. JF - Ann Rheum Dis Y1 - 2010 A1 - Ruperto, Nicolino A1 - Ozen, Seza A1 - Pistorio, Angela A1 - Dolezalova, Pavla A1 - Brogan, Paul A1 - Cabral, David A A1 - Cuttica, Ruben A1 - Khubchandani, Raju A1 - Lovell, Daniel J A1 - O'Neil, Kathleen M A1 - Quartier, Pierre A1 - Ravelli, Angelo A1 - Iusan, Silvia M A1 - Filocamo, Giovanni A1 - Magalhães, Claudia Saad A1 - Unsal, Erbil A1 - Oliveira, Sheila A1 - Bracaglia, Claudia A1 - Bagga, Arvind A1 - Stanevicha, Valda A1 - Manzoni, Silvia Magni A1 - Pratsidou, Polyxeni A1 - Lepore, Loredana A1 - Espada, Graciela A1 - Kone-Paut, Isabella A1 - Paut, Isabelle Kone A1 - Zulian, Francesco A1 - Barone, Patrizia A1 - Bircan, Zelal A1 - Maldonado, Maria del Rocio A1 - Russo, Ricardo A1 - Vilca, Iris A1 - Tullus, Kjell A1 - Cimaz, Rolando A1 - Horneff, Gerd A1 - Anton, Jordi A1 - Garay, Stella A1 - Nielsen, Susan A1 - Barbano, Giancarlo A1 - Martini, Alberto KW - Adolescent KW - Biopsy KW - Child KW - Delphi Technique KW - Granulomatosis with Polyangiitis KW - Humans KW - International Cooperation KW - Internet KW - Polyarteritis Nodosa KW - Purpura, Schoenlein-Henoch KW - Reproducibility of Results KW - Takayasu Arteritis AB -

OBJECTIVES: To report methodology and overall clinical, laboratory and radiographic characteristics for Henoch-Schönlein purpura (HSP), childhood polyarteritis nodosa (c-PAN), c-Wegener granulomatosis (c-WG) and c-Takayasu arteritis (c-TA) classification criteria.

METHODS: The preliminary Vienna 2005 consensus conference, which proposed preliminary criteria for paediatric vasculitides, was followed by a EULAR/PRINTO/PRES - supported validation project divided into three main steps. Step 1: retrospective/prospective web-data collection for HSP, c-PAN, c-WG and c-TA, with age at diagnosis

RESULTS: A total of 1183/1398 (85%) samples collected were available for analysis: 827 HSP, 150 c-PAN, 60 c-WG, 87 c-TA and 59 c-other. Prevalence, signs/symptoms, laboratory, biopsy and imaging reports were consistent with the clinical picture of the four c-vasculitides. A representative subgroup of 280 patients was blinded to the treating physician diagnosis and classified by a consensus panel, with a kappa-agreement of 0.96 for HSP (95% CI 0.84 to 1), 0.88 for c-WG (95% CI 0.76 to 0.99), 0.84 for c-TA (95% CI 0.73 to 0.96) and 0.73 for c-PAN (95% CI 0.62 to 0.84), with an overall kappa of 0.79 (95% CI 0.73 to 0.84).

CONCLUSION: EULAR/PRINTO/PRES propose validated classification criteria for HSP, c-PAN, c-WG and c-TA, with substantial/almost perfect agreement with the final consensus classification or original treating physician diagnosis.

VL - 69 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20388738?dopt=Abstract ER - TY - JOUR T1 - Methotrexate withdrawal at 6 vs 12 months in juvenile idiopathic arthritis in remission: a randomized clinical trial. JF - JAMA Y1 - 2010 A1 - Foell, Dirk A1 - Wulffraat, Nico A1 - Wedderburn, Lucy R A1 - Wittkowski, Helmut A1 - Frosch, Michael A1 - Gerss, Joachim A1 - Stanevicha, Valda A1 - Mihaylova, Dimitrina A1 - Ferriani, Virginia A1 - Tsakalidou, Florence Kanakoudi A1 - Foeldvari, Ivan A1 - Cuttica, Ruben A1 - Gonzalez, Benito A1 - Ravelli, Angelo A1 - Khubchandani, Raju A1 - Oliveira, Sheila A1 - Armbrust, Wineke A1 - Garay, Stella A1 - Vojinovic, Jelena A1 - Norambuena, Ximena A1 - Gamir, María Luz A1 - García-Consuegra, Julia A1 - Lepore, Loredana A1 - Susic, Gordana A1 - Corona, Fabrizia A1 - Dolezalova, Pavla A1 - Pistorio, Angela A1 - Martini, Alberto A1 - Ruperto, Nicolino A1 - Roth, Johannes KW - Adolescent KW - Antirheumatic Agents KW - Arthritis, Juvenile KW - ATP-Binding Cassette Transporters KW - Calgranulin B KW - Child KW - Child, Preschool KW - Female KW - Humans KW - Infant KW - Male KW - Methotrexate KW - Predictive Value of Tests KW - Prospective Studies KW - Recurrence KW - Remission Induction AB -

CONTEXT: Novel therapies have improved the remission rate in chronic inflammatory disorders including juvenile idiopathic arthritis (JIA). Therefore, strategies of tapering therapy and reliable parameters for detecting subclinical inflammation have now become challenging questions.

OBJECTIVES: To analyze whether longer methotrexate treatment during remission of JIA prevents flares after withdrawal of medication and whether specific biomarkers identify patients at risk for flares.

DESIGN, SETTING, AND PATIENTS: Prospective, open, multicenter, medication-withdrawal randomized clinical trial including 364 patients (median age, 11.0 years) with JIA recruited in 61 centers from 29 countries between February 2005 and June 2006. Patients were included at first confirmation of clinical remission while continuing medication. At the time of therapy withdrawal, levels of the phagocyte activation marker myeloid-related proteins 8 and 14 heterocomplex (MRP8/14) were determined.

INTERVENTION: Patients were randomly assigned to continue with methotrexate therapy for either 6 months (group 1 [n = 183]) or 12 months (group 2 [n = 181]) after induction of disease remission.

MAIN OUTCOME MEASURES: Primary outcome was relapse rate in the 2 treatment groups; secondary outcome was time to relapse. In a prespecified cohort analysis, the prognostic accuracy of MRP8/14 concentrations for the risk of flares was assessed.

RESULTS: Intention-to-treat analysis of the primary outcome revealed relapse within 24 months after the inclusion into the study in 98 of 183 patients (relapse rate, 56.7%) in group 1 and 94 of 181 (55.6%) in group 2. The odds ratio for group 1 vs group 2 was 1.02 (95% CI, 0.82-1.27; P = .86). The median relapse-free interval after inclusion was 21.0 months in group 1 and 23.0 months in group 2. The hazard ratio for group 1 vs group 2 was 1.07 (95% CI, 0.82-1.41; P = .61). Median follow-up duration after inclusion was 34.2 and 34.3 months in groups 1 and 2, respectively. Levels of MRP8/14 during remission were significantly higher in patients who subsequently developed flares (median, 715 [IQR, 320-1 110] ng/mL) compared with patients maintaining stable remission (400 [IQR, 220-800] ng/mL; P = .003). Low MRP8/14 levels indicated a low risk of flares within the next 3 months following the biomarker test (area under the receiver operating characteristic curve, 0.76; 95% CI, 0.62-0.90).

CONCLUSIONS: In patients with JIA in remission, a 12-month vs 6-month withdrawal of methotrexate did not reduce the relapse rate. Higher MRP8/14 concentrations were associated with risk of relapse after discontinuing methotrexate.

TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN18186313.

VL - 303 IS - 13 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20371785?dopt=Abstract ER - TY - JOUR T1 - MYH9-related disease: Report on five German families and description of a novel mutation. JF - Ann Hematol Y1 - 2010 A1 - Savoia, Anna A1 - Germeshausen, Manuela A1 - De Rocco, Daniela A1 - Henschel, Bettina A1 - Kratz, Christian P A1 - Kuhlen, Michaela A1 - Rath, Bettina A1 - Steuhl, Klaus-Peter A1 - Wermes, Cornelia A1 - Ballmaier, Matthias KW - Adult KW - Aged KW - Child KW - Chromosome Disorders KW - DNA Mutational Analysis KW - Germany KW - Humans KW - Infant KW - Molecular Motor Proteins KW - Mutation KW - Myosin Heavy Chains KW - Young Adult VL - 89 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20221761?dopt=Abstract ER - TY - JOUR T1 - Progress towards the achievement of MDG4 in the Commonwealth of Independent States: uncertain data, clear priorities. JF - Health Res Policy Syst Y1 - 2010 A1 - Cattaneo, Adriano A1 - Gafurov, Ilkhom A1 - Bomestar, Tamara A1 - Bacci, Marianna A1 - Kumar, Sanjiv A1 - Popovic, Dragoslav A1 - Tamburlini, Giorgio AB -

Data on under five mortality in the twelve countries of the Commonwealth of Independent States show important fluctuations over time due to variations in quality of data, definitions of neonatal deaths and methods of mortality estimation. Despite the uncertainties regarding mortality trends, the analysis of health and social information from different sources offers clues to identify priority areas and key strategic directions for accelerating the achievement of the 4th Millennium Development Goal. Neonatal deaths represent from 40% to over 50% of under five deaths in all these countries. Maternal mortality was above 50 per 100,000 in 2005, despite the good coverage with antenatal care and births assisted by skilled birth attendants. The scanty information on quality of perinatal care indicates widespread substandard care at all levels. Stunting in children under five is above 10% in ten out of twelve countries and coexists with emerging overweight. Exclusivity and duration of breastfeeding fall short of what is recommended. There are important inequalities in child and maternal mortality, malnutrition and access and use of health services within countries. Taken as a whole, the available information clearly indicates that priority should be given to improvement of the health of women in reproductive age and of the quality of perinatal care, including the establishment of reliable data collection systems. To achieve this, action will need to focus on strengthening the capacity of the health system to improve the technical content of service provision, and on improving access and appropriate use of services by the most disadvantaged groups. The involvement of other sectors will be necessary to improve reproductive health and nutrition at community level and to tackle inequity. Comparisons between countries with similar socioeconomic background but different health policies seem to indicate that gradual progression towards universal coverage with essential health care through a national health insurance system is associated with larger reduction of child mortality than troubled transition towards a privatized and unregulated health system.

VL - 8 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20205914?dopt=Abstract ER - TY - JOUR T1 - Therapeutic strategy in p47-phox deficient chronic granulomatous disease presenting as inflammatory bowel disease. JF - J Allergy Clin Immunol Y1 - 2010 A1 - Freudenberg, Folke A1 - Wintergerst, Uwe A1 - Roesen-Wolff, Angela A1 - Albert, Michael H A1 - Prell, Christine A1 - Strahm, Brigitte A1 - Koletzko, Sibylle A1 - Ehl, Stephan A1 - Roos, Dirk A1 - Tommasini, Alberto A1 - Ventura, Alessandro A1 - Belohradsky, Bernd H A1 - Seger, Reinhard A1 - Roesler, Joachim A1 - Güngör, Tayfun KW - Age of Onset KW - Anti-Bacterial Agents KW - Antibodies, Monoclonal KW - Child KW - Drug Therapy, Combination KW - Gene Deletion KW - Granulomatous Disease, Chronic KW - Humans KW - Inflammatory Bowel Diseases KW - Male KW - NADPH Oxidase KW - Steroids KW - Treatment Outcome KW - Vidarabine VL - 125 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20371400?dopt=Abstract ER - TY - JOUR T1 - Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies. JF - Nat Genet Y1 - 2010 A1 - Elks, Cathy E A1 - Perry, John R B A1 - Sulem, Patrick A1 - Chasman, Daniel I A1 - Franceschini, Nora A1 - He, Chunyan A1 - Lunetta, Kathryn L A1 - Visser, Jenny A A1 - Byrne, Enda M A1 - Cousminer, Diana L A1 - Gudbjartsson, Daniel F A1 - Esko, Tõnu A1 - Feenstra, Bjarke A1 - Hottenga, Jouke-Jan A1 - Koller, Daniel L A1 - Kutalik, Zoltán A1 - Lin, Peng A1 - Mangino, Massimo A1 - Marongiu, Mara A1 - McArdle, Patrick F A1 - Smith, Albert V A1 - Stolk, Lisette A1 - van Wingerden, Sophie H A1 - Zhao, Jing Hua A1 - Albrecht, Eva A1 - Corre, Tanguy A1 - Ingelsson, Erik A1 - Hayward, Caroline A1 - Magnusson, Patrik K E A1 - Smith, Erin N A1 - Ulivi, Shelia A1 - Warrington, Nicole M A1 - Zgaga, Lina A1 - Alavere, Helen A1 - Amin, Najaf A1 - Aspelund, Thor A1 - Bandinelli, Stefania A1 - Barroso, Inês A1 - Berenson, Gerald S A1 - Bergmann, Sven A1 - Blackburn, Hannah A1 - Boerwinkle, Eric A1 - Buring, Julie E A1 - Busonero, Fabio A1 - Campbell, Harry A1 - Chanock, Stephen J A1 - Chen, Wei A1 - Cornelis, Marilyn C A1 - Couper, David A1 - Coviello, Andrea D A1 - d'Adamo, Pio A1 - de Faire, Ulf A1 - de Geus, Eco J C A1 - Deloukas, Panos A1 - Döring, Angela A1 - Smith, George Davey A1 - Easton, Douglas F A1 - Eiriksdottir, Gudny A1 - Emilsson, Valur A1 - Eriksson, Johan A1 - Ferrucci, Luigi A1 - Folsom, Aaron R A1 - Foroud, Tatiana A1 - Garcia, Melissa A1 - Gasparini, Paolo A1 - Geller, Frank A1 - Gieger, Christian A1 - Gudnason, Vilmundur A1 - Hall, Per A1 - Hankinson, Susan E A1 - Ferreli, Liana A1 - Heath, Andrew C A1 - Hernandez, Dena G A1 - Hofman, Albert A1 - Hu, Frank B A1 - Illig, Thomas A1 - Järvelin, Marjo-Riitta A1 - Johnson, Andrew D A1 - Karasik, David A1 - Khaw, Kay-Tee A1 - Kiel, Douglas P A1 - Kilpeläinen, Tuomas O A1 - Kolcic, Ivana A1 - Kraft, Peter A1 - Launer, Lenore J A1 - Laven, Joop S E A1 - Li, Shengxu A1 - Liu, Jianjun A1 - Levy, Daniel A1 - Martin, Nicholas G A1 - McArdle, Wendy L A1 - Melbye, Mads A1 - Mooser, Vincent A1 - Murray, Jeffrey C A1 - Murray, Sarah S A1 - Nalls, Michael A A1 - Navarro, Pau A1 - Nelis, Mari A1 - Ness, Andrew R A1 - Northstone, Kate A1 - Oostra, Ben A A1 - Peacock, Munro A1 - Palmer, Lyle J A1 - Palotie, Aarno A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Pedersen, Nancy L A1 - Peltonen, Leena A1 - Pennell, Craig E A1 - Pharoah, Paul A1 - Polasek, Ozren A1 - Plump, Andrew S A1 - Pouta, Anneli A1 - Porcu, Eleonora A1 - Rafnar, Thorunn A1 - Rice, John P A1 - Ring, Susan M A1 - Rivadeneira, Fernando A1 - Rudan, Igor A1 - Sala, Cinzia A1 - Salomaa, Veikko A1 - Sanna, Serena A1 - Schlessinger, David A1 - Schork, Nicholas J A1 - Scuteri, Angelo A1 - Segrè, Ayellet V A1 - Shuldiner, Alan R A1 - Soranzo, Nicole A1 - Sovio, Ulla A1 - Srinivasan, Sathanur R A1 - Strachan, David P A1 - Tammesoo, Mar-Liis A1 - Tikkanen, Emmi A1 - Toniolo, Daniela A1 - Tsui, Kim A1 - Tryggvadottir, Laufey A1 - Tyrer, Jonathon A1 - Uda, Manuela A1 - van Dam, Rob M A1 - van Meurs, Joyce B J A1 - Vollenweider, Peter A1 - Waeber, Gerard A1 - Wareham, Nicholas J A1 - Waterworth, Dawn M A1 - Weedon, Michael N A1 - Wichmann, H Erich A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Wright, Alan F A1 - Young, Lauren A1 - Zhai, Guangju A1 - Zhuang, Wei Vivian A1 - Bierut, Laura J A1 - Boomsma, Dorret I A1 - Boyd, Heather A A1 - Crisponi, Laura A1 - Demerath, Ellen W A1 - van Duijn, Cornelia M A1 - Econs, Michael J A1 - Harris, Tamara B A1 - Hunter, David J A1 - Loos, Ruth J F A1 - Metspalu, Andres A1 - Montgomery, Grant W A1 - Ridker, Paul M A1 - Spector, Tim D A1 - Streeten, Elizabeth A A1 - Stefansson, Kari A1 - Thorsteinsdottir, Unnur A1 - Uitterlinden, André G A1 - Widen, Elisabeth A1 - Murabito, Joanne M A1 - Ong, Ken K A1 - Murray, Anna KW - Adolescent KW - Aging KW - Body Height KW - Body Size KW - Child KW - DNA Copy Number Variations KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Inheritance Patterns KW - Menarche KW - Obesity KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Reproducibility of Results KW - Time Factors AB -

To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.

VL - 42 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21102462?dopt=Abstract ER - TY - JOUR T1 - Two cases of Noonan syndrome with severe respiratory and gastroenteral involvement and the SOS1 mutation F623I. JF - Eur J Med Genet Y1 - 2010 A1 - Fabretto, Antonella A1 - Kutsche, Kerstin A1 - Harmsen, May-Britt A1 - Demarini, Sergio A1 - Gasparini, Paolo A1 - Fertz, Maria Cristina A1 - Zenker, Martin KW - Child, Preschool KW - Genes, ras KW - Germ-Line Mutation KW - Heterozygote KW - Humans KW - Infant KW - Infant, Newborn KW - Male KW - Mutation, Missense KW - Noonan Syndrome KW - Phenotype KW - SOS1 Protein AB -

Noonan syndrome (NS) is an autosomal dominant, inherited disorder characterized by facial dysmorphism, congenital heart defects, and reduced postnatal growth. Dysregulated RAS-MAPK signalling is the common molecular basis for NS, a genetically heterogeneous disease. Germline mutations in genes encoding small GTPases of the RAS family (KRAS and NRAS), modulators of RAS function (PTPN11, SOS1 and SHOC2) or downstream signal transducers (RAF1) are causative for NS. SOS1 is the second major gene for NS after PTPN11. Compared to patients with mutations in other genes, SOS1 mutation-positive individuals in general tend to have a more favorable outcome, with less short stature and cognitive impairment. We describe two unrelated patients with NS carrying the same heterozygous SOS1 missense mutation (c.1867T > A/p.F623I). The phenotype of both patients is remarkable as they show uncommon clinical features such as pulmonary lymphangiectasis, congenital pleural effusions, severe feeding problems, and laryngomalacia. These findings may be related to the specific mutation present in our two patients, or be part of the SOS1 phenotype. Detailed clinical assessment of large cohorts of patients with NS and SOS1 mutation is required to clarify this initial observation.

VL - 53 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20673819?dopt=Abstract ER -