TY - JOUR T1 - Gadolinium tissue deposition in the periodontal ligament of mice with reduced renal function exposed to Gd-based contrast agents. JF - Toxicol Lett Y1 - 2019 A1 - Delfino, Riccarda A1 - Biasotto, Matteo A1 - Candido, Riccardo A1 - Altissimo, Matteo A1 - Stebel, Marco A1 - Salomè, Murielle A1 - van Elteren, Johannes T A1 - Vogel Mikuš, Katarina A1 - Zennaro, Cristina A1 - Šala, Martin A1 - Addobbati, Riccardo A1 - Tromba, Giuliana A1 - Pascolo, Lorella KW - Animals KW - Contrast Media KW - Disease Models, Animal KW - Dose-Response Relationship, Drug KW - Female KW - Gadolinium KW - Gadolinium DTPA KW - Magnetic Resonance Imaging KW - Mice KW - Nephrogenic Fibrosing Dermopathy KW - Periodontal Ligament KW - Renal Insufficiency KW - Tissue Distribution AB -

Gadolinium deposition in tissue is linked to nephrogenic systemic fibrosis (NSF): a rare disorder occurring in patients with severe chronic kidney disease and associated with administration of Gd-based contrast agents (GBCAs) for Magnetic Resonance Imaging (MRI). It is suggested that the GBCAs prolonged permanence in blood in these patients may result in a Gd precipitation in peripheral or central organs, where it initiates a fibrotic process. In this study we investigated new sites of retention/precipitation of Gd in a mouse model of renal disease (5/6 nephrectomy) receiving two doses (closely after each other) of a linear GBCA. Two commercial GBCAs (Omniscan® and Magnevist®) were administered at doses slightly higher than those used in clinical practice (0.7 mmol/kg body weight, each). The animals were sacrificed one month after the last administration and the explanted organs (kidney, liver, femur, dorsal skin, teeth) were analysed by X-ray fluorescence (XRF) at two synchrotron facilities. The XRF analysis with a millimetre-sized beam at the SYRMEP beamline (Elettra, Italy) produced no detectable levels of Gd in the examined tissues, with the notable exception of the incisors of the nephrectomised mice. The XRF analyses at sub-micron resolution performed at ID21 (ESRF, France) allowed to clearly localize Gd in the periodontal ligaments of teeth both from Omniscan® and Magnevist® treated nephrectomised mice. The latter results were further confirmed by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). The study prompts that prolonged permanence of GBCAs in blood may result in Gd retention in this particular muscular tissue, opening possibilities for diagnostic applications at this level when investigating Gd-related toxicities.

VL - 301 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30476537?dopt=Abstract ER - TY - JOUR T1 - Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. JF - Lancet Neurol Y1 - 2019 AB -

BACKGROUND: Traumatic brain injury (TBI) and spinal cord injury (SCI) are increasingly recognised as global health priorities in view of the preventability of most injuries and the complex and expensive medical care they necessitate. We aimed to measure the incidence, prevalence, and years of life lived with disability (YLDs) for TBI and SCI from all causes of injury in every country, to describe how these measures have changed between 1990 and 2016, and to estimate the proportion of TBI and SCI cases caused by different types of injury.

METHODS: We used results from the Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2016 to measure the global, regional, and national burden of TBI and SCI by age and sex. We measured the incidence and prevalence of all causes of injury requiring medical care in inpatient and outpatient records, literature studies, and survey data. By use of clinical record data, we estimated the proportion of each cause of injury that required medical care that would result in TBI or SCI being considered as the nature of injury. We used literature studies to establish standardised mortality ratios and applied differential equations to convert incidence to prevalence of long-term disability. Finally, we applied GBD disability weights to calculate YLDs. We used a Bayesian meta-regression tool for epidemiological modelling, used cause-specific mortality rates for non-fatal estimation, and adjusted our results for disability experienced with comorbid conditions. We also analysed results on the basis of the Socio-demographic Index, a compound measure of income per capita, education, and fertility.

FINDINGS: In 2016, there were 27·08 million (95% uncertainty interval [UI] 24·30-30·30 million) new cases of TBI and 0·93 million (0·78-1·16 million) new cases of SCI, with age-standardised incidence rates of 369 (331-412) per 100 000 population for TBI and 13 (11-16) per 100 000 for SCI. In 2016, the number of prevalent cases of TBI was 55·50 million (53·40-57·62 million) and of SCI was 27·04 million (24·98-30·15 million). From 1990 to 2016, the age-standardised prevalence of TBI increased by 8·4% (95% UI 7·7 to 9·2), whereas that of SCI did not change significantly (-0·2% [-2·1 to 2·7]). Age-standardised incidence rates increased by 3·6% (1·8 to 5·5) for TBI, but did not change significantly for SCI (-3·6% [-7·4 to 4·0]). TBI caused 8·1 million (95% UI 6·0-10·4 million) YLDs and SCI caused 9·5 million (6·7-12·4 million) YLDs in 2016, corresponding to age-standardised rates of 111 (82-141) per 100 000 for TBI and 130 (90-170) per 100 000 for SCI. Falls and road injuries were the leading causes of new cases of TBI and SCI in most regions.

INTERPRETATION: TBI and SCI constitute a considerable portion of the global injury burden and are caused primarily by falls and road injuries. The increase in incidence of TBI over time might continue in view of increases in population density, population ageing, and increasing use of motor vehicles, motorcycles, and bicycles. The number of individuals living with SCI is expected to increase in view of population growth, which is concerning because of the specialised care that people with SCI can require. Our study was limited by data sparsity in some regions, and it will be important to invest greater resources in collection of data for TBI and SCI to improve the accuracy of future assessments.

FUNDING: Bill & Melinda Gates Foundation.

VL - 18 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30497965?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 - Genetic profile of patients with early onset inflammatory bowel disease. JF - Gene Y1 - 2018 A1 - Girardelli, Martina A1 - Basaldella, Federica A1 - Paolera, Sara Della A1 - Vuch, Josef A1 - Tommasini, Alberto A1 - Martelossi, Stefano A1 - Crovella, Sergio A1 - Bianco, Anna Monica KW - Age of Onset KW - Autophagy-Related Proteins KW - Child KW - Child, Preschool KW - Computer Simulation KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Infant KW - Inflammatory Bowel Diseases KW - Interleukin-10 KW - Male KW - Nod2 Signaling Adaptor Protein KW - Polymorphism, Single Nucleotide KW - Receptors, Interleukin KW - Receptors, Interleukin-10 KW - Sequence Analysis, DNA KW - X-Linked Inhibitor of Apoptosis Protein AB -

Inflammatory Bowel disease (IBD) is a widespread pathological condition with clinical heterogeneity and with different levels of severity. Although IBD usually occurs in young adults, onset in childhood and infancy are described in patients within the 10th and second year of age. By genome-wide association studies and meta-analysis, several genetic loci have been identified associated with an increased risk of developing IBD in Western populations with variants that may alter the normal mucosal immunity in the gastrointestinal tract. The clinical complexity and the heterogeneity of the IBD phenotype probably reflect the presence of genetic heterogeneity where different genes or combinations of them may be involved, together with environmental factors. We hypothesized that patients with early onset IBD could have either more severe genetic variants in genes associated with IBD or multiple variants in different genes. Under the multifactorial diseases is crucial to consider the small contribution of a single variant in all not only to other small variations in the same gene but also in different genes belonging to the same pathway. We performed direct gene sequencing looking for 94 variations in NOD2, ATG16L1, IL23R, IL10R, IL10 and XIAP genes previously shown as correlated with IBD both in multifactorial and in Mendelian models. All variants identified are known in literature as being associated with IBD except for three variants in the genes NOD2, IL10 and IL10RB that even though present in online databases have never been involved in association studies on IBD patients. Moreover, we coupled genetic variants identification with an accurate "in silico" analysis to verify their predictive impact on the protein structure and function. The in-silico prediction of these variants results as benign therefore even if they exhibit a very low frequency in control population being benign, they cannot be considered pathogenic as monogenic disease but fall within the multifactorial range. The variants identified in our study partially reflect the association data described in the literature but there are no significant differences with the onset of disease (VEO vs EO-IBD).

VL - 645 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29248579?dopt=Abstract ER - TY - JOUR T1 - A genetic variant of NLRP1 gene is associated with asbestos body burden in patients with malignant pleural mesothelioma. JF - J Toxicol Environ Health A Y1 - 2018 A1 - Crovella, S A1 - Moura, R R A1 - Cappellani, S A1 - Celsi, F A1 - Trevisan, E A1 - Schneider, M A1 - Brollo, A A1 - Nicastro, E M A1 - Vita, F A1 - Finotto, L A1 - Zabucchi, G A1 - Borelli, V AB -

The presence of asbestos bodies (ABs) in lung parenchyma is considered a histopathologic hallmark of past exposure to asbestos fibers, of which there was a population of longer fibers. The mechanisms underlying AB formation are complex, involving inflammatory responses and iron (Fe) metabolism. Thus, the responsiveness to AB formation is variable, with some individuals appearing to be poor AB formers. The aim of this study was to disclose the possible role of genetic variants of genes encoding inflammasome and iron metabolism proteins in the ability to form ABs in a population of 81 individuals from North East Italy, who died after having developed malignant pleural mesothelioma (MPM). This study included 86 genetic variants distributed in 10 genes involved in Fe metabolism and 7 genetic variants in two genes encoding for inflammasome molecules. Genotypes/haplotypes were compared according to the number of lung ABs. Data showed that the NLRP1 rs12150220 missense variant (H155L) was significantly correlated with numbers of ABs in MPM patients. Specifically, a low number of ABs was detected in individuals carrying the NLRP1 rs12150220 A/T genotype. Our findings suggest that the NLRP1 inflammasome might contribute in the development of lung ABs. It is postulated that the NLRP1 missense variant may be considered as one of the possible host genetic factors contributing to individual variability in coating efficiency, which needs to be taken when assessing occupational exposure to asbestos.

VL - 81 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29265930?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 identifies an association between variants in EFCAB4B gene and periodontal disease in an Italian isolated population. JF - J Periodontal Res Y1 - 2018 A1 - Bevilacqua, Lorenzo A1 - Navarra, Chiara O A1 - Pirastu, Nicola A1 - Lenarda, Roberto Di A1 - Gasparini, Paolo A1 - Robino, Antonietta KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Calcium-Binding Proteins KW - Chronic Periodontitis KW - DNA KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Italy KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Regression Analysis KW - Young Adult AB -

BACKGROUND AND OBJECTIVE: Periodontitis in one of the most prevalent dental diseases. Despite numerous studies have investigated its aetiopathogenetic factors, few works have focused on its genetic predisposition and most of them took into account only candidate genes. Therefore, we conducted a Genome Wide Association Study in an Italian isolated population aimed at uncovering genetic variants that predispose to this disorder.

METHODS: Diagnosis of chronic periodontitis was made following the criteria of the American Academy of Periodontology. Patients with chronic periodontitis were grouped into different categories: slight, severe, localized and generalized. A control group composed by people without signs of periodontitis or gingivitis was defined. DNA was genotyped using 370k Illumina chips. Linear mixed model regression was used to test the association between each single nucleotide polymorphism (SNP) (independent variable) and the periodontitis status (dependent variable), controlling for confounders sex, age and smoking. The genomic kinship matrix was also used as random effect.

RESULTS: Four SNPs on the gene EFCAB4B resulted significantly associated to localized periodontitis (P < 5 × 10 ), with the best hit on the rs242016 SNP (P = 1.5 × 10 ).

CONCLUSION: We have identified a novel significant association between the EFCAB4B gene and localized periodontitis. These results open a new perspective in the understanding of genetic factors contributing to this common disorder.

VL - 53 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30284742?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 - A Giant Ovarian Cyst in an Adolescent. JF - J Pediatr Y1 - 2018 A1 - Corrias, Francesca A1 - Pederiva, Federica A1 - Cozzi, Giorgio A1 - Ammar, Lydie A1 - Cattaruzzi, Elisabetta A1 - Lembo, Maria Antonietta A1 - Barbi, Egidio KW - Child KW - Cystadenoma, Serous KW - Female KW - Humans KW - Ovarian Neoplasms VL - 199 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29731358?dopt=Abstract ER - TY - JOUR T1 - Girl With Chest Pain. JF - Ann Emerg Med Y1 - 2018 A1 - Scarpa, Maria-Grazia A1 - Rabach, Ingrid A1 - Canuto, Arianna A1 - Sanabor, Daniela A1 - Barbi, Egidio A1 - Schleef, Jurgen VL - 72 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30031519?dopt=Abstract ER - TY - JOUR T1 - A Girl with Delayed Puberty and Bumpy Lips. JF - J Pediatr Y1 - 2018 A1 - Andrade, Stefanny A1 - Sirchia, Fabio A1 - Faleschini, Elena A1 - Barbi, Egidio KW - Adolescent KW - Exons KW - Female KW - Genes, Dominant KW - Humans KW - Lip KW - Multiple Endocrine Neoplasia Type 2b KW - Neoplasm Metastasis KW - Puberty, Delayed KW - Thyroid Neoplasms KW - Thyroidectomy KW - Tongue VL - 203 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30025668?dopt=Abstract ER - TY - JOUR T1 - Global, regional, and national age-sex-specific mortality and life expectancy, 1950-2017: a systematic analysis for the Global Burden of Disease Study 2017. JF - Lancet Y1 - 2018 KW - Adolescent KW - Adult KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Child KW - Child, Preschool KW - Female KW - Global Burden of Disease KW - Global Health KW - Humans KW - Infant KW - Infant, Newborn KW - Life Expectancy KW - Male KW - Middle Aged KW - Mortality KW - Sex Distribution KW - Socioeconomic Factors KW - Young Adult AB -

BACKGROUND: Assessments of age-specific mortality and life expectancy have been done by the UN Population Division, Department of Economics and Social Affairs (UNPOP), the United States Census Bureau, WHO, and as part of previous iterations of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD). Previous iterations of the GBD used population estimates from UNPOP, which were not derived in a way that was internally consistent with the estimates of the numbers of deaths in the GBD. The present iteration of the GBD, GBD 2017, improves on previous assessments and provides timely estimates of the mortality experience of populations globally.

METHODS: The GBD uses all available data to produce estimates of mortality rates between 1950 and 2017 for 23 age groups, both sexes, and 918 locations, including 195 countries and territories and subnational locations for 16 countries. Data used include vital registration systems, sample registration systems, household surveys (complete birth histories, summary birth histories, sibling histories), censuses (summary birth histories, household deaths), and Demographic Surveillance Sites. In total, this analysis used 8259 data sources. Estimates of the probability of death between birth and the age of 5 years and between ages 15 and 60 years are generated and then input into a model life table system to produce complete life tables for all locations and years. Fatal discontinuities and mortality due to HIV/AIDS are analysed separately and then incorporated into the estimation. We analyse the relationship between age-specific mortality and development status using the Socio-demographic Index, a composite measure based on fertility under the age of 25 years, education, and income. There are four main methodological improvements in GBD 2017 compared with GBD 2016: 622 additional data sources have been incorporated; new estimates of population, generated by the GBD study, are used; statistical methods used in different components of the analysis have been further standardised and improved; and the analysis has been extended backwards in time by two decades to start in 1950.

FINDINGS: Globally, 18·7% (95% uncertainty interval 18·4-19·0) of deaths were registered in 1950 and that proportion has been steadily increasing since, with 58·8% (58·2-59·3) of all deaths being registered in 2015. At the global level, between 1950 and 2017, life expectancy increased from 48·1 years (46·5-49·6) to 70·5 years (70·1-70·8) for men and from 52·9 years (51·7-54·0) to 75·6 years (75·3-75·9) for women. Despite this overall progress, there remains substantial variation in life expectancy at birth in 2017, which ranges from 49·1 years (46·5-51·7) for men in the Central African Republic to 87·6 years (86·9-88·1) among women in Singapore. The greatest progress across age groups was for children younger than 5 years; under-5 mortality dropped from 216·0 deaths (196·3-238·1) per 1000 livebirths in 1950 to 38·9 deaths (35·6-42·83) per 1000 livebirths in 2017, with huge reductions across countries. Nevertheless, there were still 5·4 million (5·2-5·6) deaths among children younger than 5 years in the world in 2017. Progress has been less pronounced and more variable for adults, especially for adult males, who had stagnant or increasing mortality rates in several countries. The gap between male and female life expectancy between 1950 and 2017, while relatively stable at the global level, shows distinctive patterns across super-regions and has consistently been the largest in central Europe, eastern Europe, and central Asia, and smallest in south Asia. Performance was also variable across countries and time in observed mortality rates compared with those expected on the basis of development.

INTERPRETATION: This analysis of age-sex-specific mortality shows that there are remarkably complex patterns in population mortality across countries. The findings of this study highlight global successes, such as the large decline in under-5 mortality, which reflects significant local, national, and global commitment and investment over several decades. However, they also bring attention to mortality patterns that are a cause for concern, particularly among adult men and, to a lesser extent, women, whose mortality rates have stagnated in many countries over the time period of this study, and in some cases are increasing.

FUNDING: Bill & Melinda Gates Foundation.

VL - 392 IS - 10159 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30496102?dopt=Abstract ER - TY - JOUR T1 - Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. JF - Lancet Y1 - 2018 KW - Adolescent KW - Adult KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Cause of Death KW - Child KW - Child, Preschool KW - Female KW - Global Burden of Disease KW - Global Health KW - Humans KW - Infant KW - Infant, Newborn KW - Life Expectancy KW - Male KW - Middle Aged KW - Sex Distribution KW - Socioeconomic Factors KW - Young Adult AB -

BACKGROUND: Global development goals increasingly rely on country-specific estimates for benchmarking a nation's progress. To meet this need, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 estimated global, regional, national, and, for selected locations, subnational cause-specific mortality beginning in the year 1980. Here we report an update to that study, making use of newly available data and improved methods. GBD 2017 provides a comprehensive assessment of cause-specific mortality for 282 causes in 195 countries and territories from 1980 to 2017.

METHODS: The causes of death database is composed of vital registration (VR), verbal autopsy (VA), registry, survey, police, and surveillance data. GBD 2017 added ten VA studies, 127 country-years of VR data, 502 cancer-registry country-years, and an additional surveillance country-year. Expansions of the GBD cause of death hierarchy resulted in 18 additional causes estimated for GBD 2017. Newly available data led to subnational estimates for five additional countries-Ethiopia, Iran, New Zealand, Norway, and Russia. Deaths assigned International Classification of Diseases (ICD) codes for non-specific, implausible, or intermediate causes of death were reassigned to underlying causes by redistribution algorithms that were incorporated into uncertainty estimation. We used statistical modelling tools developed for GBD, including the Cause of Death Ensemble model (CODEm), to generate cause fractions and cause-specific death rates for each location, year, age, and sex. Instead of using UN estimates as in previous versions, GBD 2017 independently estimated population size and fertility rate for all locations. Years of life lost (YLLs) were then calculated as the sum of each death multiplied by the standard life expectancy at each age. All rates reported here are age-standardised.

FINDINGS: At the broadest grouping of causes of death (Level 1), non-communicable diseases (NCDs) comprised the greatest fraction of deaths, contributing to 73·4% (95% uncertainty interval [UI] 72·5-74·1) of total deaths in 2017, while communicable, maternal, neonatal, and nutritional (CMNN) causes accounted for 18·6% (17·9-19·6), and injuries 8·0% (7·7-8·2). Total numbers of deaths from NCD causes increased from 2007 to 2017 by 22·7% (21·5-23·9), representing an additional 7·61 million (7·20-8·01) deaths estimated in 2017 versus 2007. The death rate from NCDs decreased globally by 7·9% (7·0-8·8). The number of deaths for CMNN causes decreased by 22·2% (20·0-24·0) and the death rate by 31·8% (30·1-33·3). Total deaths from injuries increased by 2·3% (0·5-4·0) between 2007 and 2017, and the death rate from injuries decreased by 13·7% (12·2-15·1) to 57·9 deaths (55·9-59·2) per 100 000 in 2017. Deaths from substance use disorders also increased, rising from 284 000 deaths (268 000-289 000) globally in 2007 to 352 000 (334 000-363 000) in 2017. Between 2007 and 2017, total deaths from conflict and terrorism increased by 118·0% (88·8-148·6). A greater reduction in total deaths and death rates was observed for some CMNN causes among children younger than 5 years than for older adults, such as a 36·4% (32·2-40·6) reduction in deaths from lower respiratory infections for children younger than 5 years compared with a 33·6% (31·2-36·1) increase in adults older than 70 years. Globally, the number of deaths was greater for men than for women at most ages in 2017, except at ages older than 85 years. Trends in global YLLs reflect an epidemiological transition, with decreases in total YLLs from enteric infections, respiratory infections and tuberculosis, and maternal and neonatal disorders between 1990 and 2017; these were generally greater in magnitude at the lowest levels of the Socio-demographic Index (SDI). At the same time, there were large increases in YLLs from neoplasms and cardiovascular diseases. YLL rates decreased across the five leading Level 2 causes in all SDI quintiles. The leading causes of YLLs in 1990-neonatal disorders, lower respiratory infections, and diarrhoeal diseases-were ranked second, fourth, and fifth, in 2017. Meanwhile, estimated YLLs increased for ischaemic heart disease (ranked first in 2017) and stroke (ranked third), even though YLL rates decreased. Population growth contributed to increased total deaths across the 20 leading Level 2 causes of mortality between 2007 and 2017. Decreases in the cause-specific mortality rate reduced the effect of population growth for all but three causes: substance use disorders, neurological disorders, and skin and subcutaneous diseases.

INTERPRETATION: Improvements in global health have been unevenly distributed among populations. Deaths due to injuries, substance use disorders, armed conflict and terrorism, neoplasms, and cardiovascular disease are expanding threats to global health. For causes of death such as lower respiratory and enteric infections, more rapid progress occurred for children than for the oldest adults, and there is continuing disparity in mortality rates by sex across age groups. Reductions in the death rate of some common diseases are themselves slowing or have ceased, primarily for NCDs, and the death rate for selected causes has increased in the past decade.

FUNDING: Bill & Melinda Gates Foundation.

VL - 392 IS - 10159 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30496103?dopt=Abstract ER - TY - JOUR T1 - Global, regional, and national burden of meningitis, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. JF - Lancet Neurol Y1 - 2018 AB -

BACKGROUND: Acute meningitis has a high case-fatality rate and survivors can have severe lifelong disability. We aimed to provide a comprehensive assessment of the levels and trends of global meningitis burden that could help to guide introduction, continuation, and ongoing development of vaccines and treatment programmes.

METHODS: The Global Burden of Diseases, Injuries, and Risk Factors (GBD) 2016 study estimated meningitis burden due to one of four types of cause: pneumococcal, meningococcal, Haemophilus influenzae type b, and a residual category of other causes. Cause-specific mortality estimates were generated via cause of death ensemble modelling of vital registration and verbal autopsy data that were subject to standardised data processing algorithms. Deaths were multiplied by the GBD standard life expectancy at age of death to estimate years of life lost, the mortality component of disability-adjusted life-years (DALYs). A systematic analysis of relevant publications and hospital and claims data was used to estimate meningitis incidence via a Bayesian meta-regression tool. Meningitis deaths and cases were split between causes with meta-regressions of aetiological proportions of mortality and incidence, respectively. Probabilities of long-term impairment by cause of meningitis were applied to survivors and used to estimate years of life lived with disability (YLDs). We assessed the relationship between burden metrics and Socio-demographic Index (SDI), a composite measure of development based on fertility, income, and education.

FINDINGS: Global meningitis deaths decreased by 21·0% from 1990 to 2016, from 403 012 (95% uncertainty interval [UI] 319 426-458 514) to 318 400 (265 218-408 705). Incident cases globally increased from 2·50 million (95% UI 2·19-2·91) in 1990 to 2·82 million (2·46-3·31) in 2016. Meningitis mortality and incidence were closely related to SDI. The highest mortality rates and incidence rates were found in the peri-Sahelian countries that comprise the African meningitis belt, with six of the ten countries with the largest number of cases and deaths being located within this region. Haemophilus influenzae type b was the most common cause of incident meningitis in 1990, at 780 070 cases (95% UI 613 585-978 219) globally, but decreased the most (-49·1%) to become the least common cause in 2016, with 397 297 cases (291 076-533 662). Meningococcus was the leading cause of meningitis mortality in 1990 (192 833 deaths [95% UI 153 358-221 503] globally), whereas other meningitis was the leading cause for both deaths (136 423 [112 682-178 022]) and incident cases (1·25 million [1·06-1·49]) in 2016. Pneumococcus caused the largest number of YLDs (634 458 [444 787-839 749]) in 2016, owing to its more severe long-term effects on survivors. Globally in 2016, 1·48 million (1·04-1·96) YLDs were due to meningitis compared with 21·87 million (18·20-28·28) DALYs, indicating that the contribution of mortality to meningitis burden is far greater than the contribution of disabling outcomes.

INTERPRETATION: Meningitis burden remains high and progress lags substantially behind that of other vaccine-preventable diseases. Particular attention should be given to developing vaccines with broader coverage against the causes of meningitis, making these vaccines affordable in the most affected countries, improving vaccine uptake, improving access to low-cost diagnostics and therapeutics, and improving support for disabled survivors. Substantial uncertainty remains around pathogenic causes and risk factors for meningitis. Ongoing, active cause-specific surveillance of meningitis is crucial to continue and to improve monitoring of meningitis burdens and trends throughout the world.

FUNDING: Bill & Melinda Gates Foundation.

VL - 17 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30507391?dopt=Abstract ER - TY - JOUR T1 - Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Stu JF - Lancet Y1 - 2018 KW - Adolescent KW - Adult KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Child KW - Child, Preschool KW - Disabled Persons KW - Environmental Exposure KW - Female KW - Global Burden of Disease KW - Global Health KW - Health Risk Behaviors KW - Humans KW - Infant KW - Infant, Newborn KW - Life Expectancy KW - Male KW - Metabolic Diseases KW - Middle Aged KW - Occupational Diseases KW - Occupational Exposure KW - Quality-Adjusted Life Years KW - Risk Assessment KW - Sex Distribution KW - Socioeconomic Factors KW - Young Adult AB -

BACKGROUND: The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk-outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk-outcome pairs, and new data on risk exposure levels and risk-outcome associations.

METHODS: We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk-outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017.

FINDINGS: In 2017, 34·1 million (95% uncertainty interval [UI] 33·3-35·0) deaths and 1·21 billion (1·14-1·28) DALYs were attributable to GBD risk factors. Globally, 61·0% (59·6-62·4) of deaths and 48·3% (46·3-50·2) of DALYs were attributed to the GBD 2017 risk factors. When ranked by risk-attributable DALYs, high systolic blood pressure (SBP) was the leading risk factor, accounting for 10·4 million (9·39-11·5) deaths and 218 million (198-237) DALYs, followed by smoking (7·10 million [6·83-7·37] deaths and 182 million [173-193] DALYs), high fasting plasma glucose (6·53 million [5·23-8·23] deaths and 171 million [144-201] DALYs), high body-mass index (BMI; 4·72 million [2·99-6·70] deaths and 148 million [98·6-202] DALYs), and short gestation for birthweight (1·43 million [1·36-1·51] deaths and 139 million [131-147] DALYs). In total, risk-attributable DALYs declined by 4·9% (3·3-6·5) between 2007 and 2017. In the absence of demographic changes (ie, population growth and ageing), changes in risk exposure and risk-deleted DALYs would have led to a 23·5% decline in DALYs during that period. Conversely, in the absence of changes in risk exposure and risk-deleted DALYs, demographic changes would have led to an 18·6% increase in DALYs during that period. The ratios of observed risk exposure levels to exposure levels expected based on SDI (O/E ratios) increased globally for unsafe drinking water and household air pollution between 1990 and 2017. This result suggests that development is occurring more rapidly than are changes in the underlying risk structure in a population. Conversely, nearly universal declines in O/E ratios for smoking and alcohol use indicate that, for a given SDI, exposure to these risks is declining. In 2017, the leading Level 4 risk factor for age-standardised DALY rates was high SBP in four super-regions: central Europe, eastern Europe, and central Asia; north Africa and Middle East; south Asia; and southeast Asia, east Asia, and Oceania. The leading risk factor in the high-income super-region was smoking, in Latin America and Caribbean was high BMI, and in sub-Saharan Africa was unsafe sex. O/E ratios for unsafe sex in sub-Saharan Africa were notably high, and those for alcohol use in north Africa and the Middle East were notably low.

INTERPRETATION: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning.

FUNDING: Bill & Melinda Gates Foundation.

VL - 392 IS - 10159 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30496105?dopt=Abstract ER - TY - JOUR T1 - Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. JF - Lancet Y1 - 2018 KW - Aged KW - Communicable Diseases KW - Disabled Persons KW - Female KW - Global Burden of Disease KW - Health Status KW - Healthy Lifestyle KW - Humans KW - Life Expectancy KW - Male KW - Mortality KW - Mortality, Premature KW - Prevalence KW - Quality-Adjusted Life Years KW - Risk Factors KW - Socioeconomic Factors KW - Wounds and Injuries AB -

BACKGROUND: How long one lives, how many years of life are spent in good and poor health, and how the population's state of health and leading causes of disability change over time all have implications for policy, planning, and provision of services. We comparatively assessed the patterns and trends of healthy life expectancy (HALE), which quantifies the number of years of life expected to be lived in good health, and the complementary measure of disability-adjusted life-years (DALYs), a composite measure of disease burden capturing both premature mortality and prevalence and severity of ill health, for 359 diseases and injuries for 195 countries and territories over the past 28 years.

METHODS: We used data for age-specific mortality rates, years of life lost (YLLs) due to premature mortality, and years lived with disability (YLDs) from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 to calculate HALE and DALYs from 1990 to 2017. We calculated HALE using age-specific mortality rates and YLDs per capita for each location, age, sex, and year. We calculated DALYs for 359 causes as the sum of YLLs and YLDs. We assessed how observed HALE and DALYs differed by country and sex from expected trends based on Socio-demographic Index (SDI). We also analysed HALE by decomposing years of life gained into years spent in good health and in poor health, between 1990 and 2017, and extra years lived by females compared with males.

FINDINGS: Globally, from 1990 to 2017, life expectancy at birth increased by 7·4 years (95% uncertainty interval 7·1-7·8), from 65·6 years (65·3-65·8) in 1990 to 73·0 years (72·7-73·3) in 2017. The increase in years of life varied from 5·1 years (5·0-5·3) in high SDI countries to 12·0 years (11·3-12·8) in low SDI countries. Of the additional years of life expected at birth, 26·3% (20·1-33·1) were expected to be spent in poor health in high SDI countries compared with 11·7% (8·8-15·1) in low-middle SDI countries. HALE at birth increased by 6·3 years (5·9-6·7), from 57·0 years (54·6-59·1) in 1990 to 63·3 years (60·5-65·7) in 2017. The increase varied from 3·8 years (3·4-4·1) in high SDI countries to 10·5 years (9·8-11·2) in low SDI countries. Even larger variations in HALE than these were observed between countries, ranging from 1·0 year (0·4-1·7) in Saint Vincent and the Grenadines (62·4 years [59·9-64·7] in 1990 to 63·5 years [60·9-65·8] in 2017) to 23·7 years (21·9-25·6) in Eritrea (30·7 years [28·9-32·2] in 1990 to 54·4 years [51·5-57·1] in 2017). In most countries, the increase in HALE was smaller than the increase in overall life expectancy, indicating more years lived in poor health. In 180 of 195 countries and territories, females were expected to live longer than males in 2017, with extra years lived varying from 1·4 years (0·6-2·3) in Algeria to 11·9 years (10·9-12·9) in Ukraine. Of the extra years gained, the proportion spent in poor health varied largely across countries, with less than 20% of additional years spent in poor health in Bosnia and Herzegovina, Burundi, and Slovakia, whereas in Bahrain all the extra years were spent in poor health. In 2017, the highest estimate of HALE at birth was in Singapore for both females (75·8 years [72·4-78·7]) and males (72·6 years [69·8-75·0]) and the lowest estimates were in Central African Republic (47·0 years [43·7-50·2] for females and 42·8 years [40·1-45·6] for males). Globally, in 2017, the five leading causes of DALYs were neonatal disorders, ischaemic heart disease, stroke, lower respiratory infections, and chronic obstructive pulmonary disease. Between 1990 and 2017, age-standardised DALY rates decreased by 41·3% (38·8-43·5) for communicable diseases and by 49·8% (47·9-51·6) for neonatal disorders. For non-communicable diseases, global DALYs increased by 40·1% (36·8-43·0), although age-standardised DALY rates decreased by 18·1% (16·0-20·2).

INTERPRETATION: With increasing life expectancy in most countries, the question of whether the additional years of life gained are spent in good health or poor health has been increasingly relevant because of the potential policy implications, such as health-care provisions and extending retirement ages. In some locations, a large proportion of those additional years are spent in poor health. Large inequalities in HALE and disease burden exist across countries in different SDI quintiles and between sexes. The burden of disabling conditions has serious implications for health system planning and health-related expenditures. Despite the progress made in reducing the burden of communicable diseases and neonatal disorders in low SDI countries, the speed of this progress could be increased by scaling up proven interventions. The global trends among non-communicable diseases indicate that more effort is needed to maximise HALE, such as risk prevention and attention to upstream determinants of health.

FUNDING: Bill & Melinda Gates Foundation.

VL - 392 IS - 10159 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30415748?dopt=Abstract ER - TY - JOUR T1 - Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. JF - Lancet Y1 - 2018 KW - Adolescent KW - Adult KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Child KW - Child, Preschool KW - Disabled Persons KW - Female KW - Global Burden of Disease KW - Global Health KW - Humans KW - Incidence KW - Infant KW - Infant, Newborn KW - Life Expectancy KW - Male KW - Middle Aged KW - Morbidity KW - Prevalence KW - Sex Distribution KW - Socioeconomic Factors KW - Wounds and Injuries KW - Young Adult AB -

BACKGROUND: The Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) includes a comprehensive assessment of incidence, prevalence, and years lived with disability (YLDs) for 354 causes in 195 countries and territories from 1990 to 2017. Previous GBD studies have shown how the decline of mortality rates from 1990 to 2016 has led to an increase in life expectancy, an ageing global population, and an expansion of the non-fatal burden of disease and injury. These studies have also shown how a substantial portion of the world's population experiences non-fatal health loss with considerable heterogeneity among different causes, locations, ages, and sexes. Ongoing objectives of the GBD study include increasing the level of estimation detail, improving analytical strategies, and increasing the amount of high-quality data.

METHODS: We estimated incidence and prevalence for 354 diseases and injuries and 3484 sequelae. We used an updated and extensive body of literature studies, survey data, surveillance data, inpatient admission records, outpatient visit records, and health insurance claims, and additionally used results from cause of death models to inform estimates using a total of 68 781 data sources. Newly available clinical data from India, Iran, Japan, Jordan, Nepal, China, Brazil, Norway, and Italy were incorporated, as well as updated claims data from the USA and new claims data from Taiwan (province of China) and Singapore. We used DisMod-MR 2.1, a Bayesian meta-regression tool, as the main method of estimation, ensuring consistency between rates of incidence, prevalence, remission, and cause of death for each condition. YLDs were estimated as the product of a prevalence estimate and a disability weight for health states of each mutually exclusive sequela, adjusted for comorbidity. We updated the Socio-demographic Index (SDI), a summary development indicator of income per capita, years of schooling, and total fertility rate. Additionally, we calculated differences between male and female YLDs to identify divergent trends across sexes. GBD 2017 complies with the Guidelines for Accurate and Transparent Health Estimates Reporting.

FINDINGS: Globally, for females, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and haemoglobinopathies and haemolytic anaemias in both 1990 and 2017. For males, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and tuberculosis including latent tuberculosis infection in both 1990 and 2017. In terms of YLDs, low back pain, headache disorders, and dietary iron deficiency were the leading Level 3 causes of YLD counts in 1990, whereas low back pain, headache disorders, and depressive disorders were the leading causes in 2017 for both sexes combined. All-cause age-standardised YLD rates decreased by 3·9% (95% uncertainty interval [UI] 3·1-4·6) from 1990 to 2017; however, the all-age YLD rate increased by 7·2% (6·0-8·4) while the total sum of global YLDs increased from 562 million (421-723) to 853 million (642-1100). The increases for males and females were similar, with increases in all-age YLD rates of 7·9% (6·6-9·2) for males and 6·5% (5·4-7·7) for females. We found significant differences between males and females in terms of age-standardised prevalence estimates for multiple causes. The causes with the greatest relative differences between sexes in 2017 included substance use disorders (3018 cases [95% UI 2782-3252] per 100 000 in males vs s1400 [1279-1524] per 100 000 in females), transport injuries (3322 [3082-3583] vs 2336 [2154-2535]), and self-harm and interpersonal violence (3265 [2943-3630] vs 5643 [5057-6302]).

INTERPRETATION: Global all-cause age-standardised YLD rates have improved only slightly over a period spanning nearly three decades. However, the magnitude of the non-fatal disease burden has expanded globally, with increasing numbers of people who have a wide spectrum of conditions. A subset of conditions has remained globally pervasive since 1990, whereas other conditions have displayed more dynamic trends, with different ages, sexes, and geographies across the globe experiencing varying burdens and trends of health loss. This study emphasises how global improvements in premature mortality for select conditions have led to older populations with complex and potentially expensive diseases, yet also highlights global achievements in certain domains of disease and injury.

FUNDING: Bill & Melinda Gates Foundation.

VL - 392 IS - 10159 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30496104?dopt=Abstract ER - TY - JOUR T1 - Gut microbiota characterisation in obese patients before and after bariatric surgery. JF - Benef Microbes Y1 - 2018 A1 - Campisciano, G A1 - Palmisano, S A1 - Cason, C A1 - Giuricin, M A1 - Silvestri, M A1 - Guerra, M A1 - Macor, D A1 - De Manzini, N A1 - Crocé, L S A1 - Comar, M KW - Adult KW - Bariatric Surgery KW - Gastrointestinal Microbiome KW - Humans KW - Laparoscopy KW - Microbiota KW - Middle Aged KW - Obesity KW - Young Adult AB -

Intestinal microbiota analysis of obese patients after bariatric surgery showed that Proteobacteria decreased after laparoscopic sleeve gastrectomy (SG), while it increased after laparoscopic gastric bypass (LGB). Comparing to normal weight (NW) patients, obese patients that were selected for SG showed an almost equal amount of Firmicutes and Bacteroidetes and the ratio was not affected by the surgery. Obese patients before LGB showed a predominance of Bacteroidetes, whose amount regained a relative abundance similar to NW patients after surgery. Obese patients before LGB showed the predominance of Bacteroides, which decreased after surgery in favour of Prevotella, a bacterium associated with a healthy diet. The bacteria detected at the highest percentages belonged to biofilm forming species. In conclusion, in this study, we found that the characterization of the gut microbial communities and the modality of mucosal colonisation have a central role as markers for the clinical management of obesity and promote the maintenance of good health and the weight loss.

VL - 9 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29482339?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 - Gray platelet syndrome: Novel mutations of the NBEAL2 gene. JF - Am J Hematol Y1 - 2017 A1 - Bottega, Roberta A1 - Nicchia, Elena A1 - Alfano, Caterina A1 - Glembotsky, Ana C A1 - Pastore, Annalisa A1 - Bertaggia-Calderara, Debora A1 - Bisig, Bettina A1 - Duchosal, Michel A A1 - Arbesú, Guillermo A1 - Alberio, Lorenzo A1 - Heller, Paula G A1 - Savoia, Anna KW - Adult KW - Alleles KW - Blood Proteins KW - Child KW - Female KW - Gene Expression KW - Gene Frequency KW - Genotype KW - Gray Platelet Syndrome KW - Humans KW - Male KW - Mutation KW - Phenotype KW - Platelet Aggregation KW - Platelet Count KW - Platelet Membrane Glycoproteins VL - 92 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27870194?dopt=Abstract ER - TY - JOUR T1 - Guidelines of the Italian Society of Videosurgery in Infancy for the minimally invasive treatment of the esophageal atresia. JF - Pediatr Med Chir Y1 - 2017 A1 - Chiarenza, Salvatore Fabio A1 - Conighi, Maria Luisa A1 - Conforti, Andrea A1 - Esposito, Ciro A1 - Escolino, Maria A1 - Beretta, Fabio A1 - Cheli, Maurizio A1 - Di Benedetto, Vincenzo A1 - Scuderi, Maria Grazia A1 - Casadio, Giovanni A1 - Marzaro, Maurizio A1 - Fascetti, Leon Francesco A1 - Vella, Claudio A1 - Bleve, Cosimo A1 - Codric, Daniela A1 - Caione, Paolo A1 - Bagolan, Pietro KW - Esophageal Atresia KW - Humans KW - Infant KW - Minimally Invasive Surgical Procedures KW - Video-Assisted Surgery AB -

Not available.

VL - 39 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29034656?dopt=Abstract ER - TY - JOUR T1 - Guidelines of the Italian Society of Videosurgery in Infancy for the minimally invasive treatment of the ureteropelvic-junction obstruction. JF - Pediatr Med Chir Y1 - 2017 A1 - Chiarenza, Salvatore Fabio A1 - Bleve, Cosimo A1 - Esposito, Ciro A1 - Escolino, Maria A1 - Beretta, Fabio A1 - Cheli, Maurizio A1 - Di Benedetto, Vincenzo A1 - Scuderi, Maria Grazia A1 - Casadio, Giovanni A1 - Marzaro, Maurizio A1 - Fascetti, Leon Francesco A1 - Bagolan, Pietro A1 - Vella, Claudio A1 - Conighi, Maria Luisa A1 - Codric, Daniela A1 - Nappo, Simona A1 - Caione, Paolo KW - Humans KW - Infant KW - Kidney Pelvis KW - Minimally Invasive Surgical Procedures KW - Ureteral Obstruction KW - Video-Assisted Surgery AB -

Not available.

VL - 39 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29034657?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 - Geranylgeraniol and Neurological Impairment: Involvement of Apoptosis and Mitochondrial Morphology. JF - Int J Mol Sci Y1 - 2016 A1 - Marcuzzi, Annalisa A1 - Piscianz, Elisa A1 - Zweyer, Marina A1 - Bortul, Roberta A1 - Loganes, Claudia A1 - Girardelli, Martina A1 - Baj, Gabriele A1 - Monasta, Lorenzo A1 - Celeghini, Claudio AB -

Deregulation of the cholesterol pathway is an anomaly observed in human diseases, many of which have in common neurological involvement and unknown pathogenesis. In this study we have used Mevalonate Kinase Deficiency (MKD) as a disease-model in order to investigate the link between the deregulation of the mevalonate pathway and the consequent neurodegeneration. The blocking of the mevalonate pathway in a neuronal cell line (Daoy), using statins or mevalonate, induced an increase in the expression of the inflammasome gene (NLRP3) and programmed cell death related to mitochondrial dysfunction. The morphology of the mitochondria changed, clearly showing the damage induced by oxidative stress and the decreased membrane potential associated with the alterations of the mitochondrial function. The co-administration of geranylgeraniol (GGOH) reduced the inflammatory marker and the damage of the mitochondria, maintaining its shape and components. Our data allow us to speculate about the mechanism by which isoprenoids are able to rescue the inflammatory marker in neuronal cells, independently from the block of the mevalonate pathway, and about the fact that cell death is mitochondria-related.

VL - 17 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26978350?dopt=Abstract ER - TY - JOUR T1 - Giant Cerebellar Lesion in a Patient With Purulent Ear Drainage. JF - JAMA Otolaryngol Head Neck Surg Y1 - 2016 A1 - Mandalà, Marco A1 - Muzzi, Enrico A1 - Trabalzini, Franco VL - 142 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27100394?dopt=Abstract ER - TY - JOUR T1 - Global diversity in the TAS2R38 bitter taste receptor: revisiting a classic evolutionary PROPosal. JF - Sci Rep Y1 - 2016 A1 - Risso, Davide S A1 - Mezzavilla, Massimo A1 - Pagani, Luca A1 - Robino, Antonietta A1 - Morini, Gabriella A1 - Tofanelli, Sergio A1 - Carrai, Maura A1 - Campa, Daniele A1 - Barale, Roberto A1 - Caradonna, Fabio A1 - Gasparini, Paolo A1 - Luiselli, Donata A1 - Wooding, Stephen A1 - Drayna, Dennis AB -

The ability to taste phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP) is a polymorphic trait mediated by the TAS2R38 bitter taste receptor gene. It has long been hypothesized that global genetic diversity at this locus evolved under pervasive pressures from balancing natural selection. However, recent high-resolution population genetic studies of TAS2Rs suggest that demographic events have played a critical role in the evolution of these genes. We here utilized the largest TAS2R38 database yet analyzed, consisting of 5,589 individuals from 105 populations, to examine natural selection, haplotype frequencies and linkage disequilibrium to estimate the effects of both selection and demography on contemporary patterns of variation at this locus. We found signs of an ancient balancing selection acting on this gene but no post Out-Of-Africa departures from neutrality, implying that the current observed patterns of variation can be predominantly explained by demographic, rather than selective events. In addition, we found signatures of ancient selective forces acting on different African TAS2R38 haplotypes. Collectively our results provide evidence for a relaxation of recent selective forces acting on this gene and a revised hypothesis for the origins of the present-day worldwide distribution of TAS2R38 haplotypes.

VL - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27138342?dopt=Abstract ER - TY - JOUR T1 - The Great Pretender: Pediatric Wandering Spleen: Two Case Reports and Review of the Literature. JF - Pediatr Emerg Care Y1 - 2016 A1 - Radillo, Lucia A1 - Taddio, Andrea A1 - Ghirardo, Sergio A1 - Bramuzzo, Matteo A1 - Pederiva, Federica A1 - Maschio, Massimo A1 - Barbi, Egidio AB -

Wandering spleen is a rare condition, typically not only due to embryological defects of the splenic ligaments, but also secondary to trauma and splenomegaly. The most common presentation is acute abdomen with a mobile abdominal mass or recurrent abdominal pain. However, the spleen may be temporary in its normal position, and patients could be asymptomatic. A familiarity, if present, strengthens the diagnostic suspect.Abdominal ultrasonography and computed tomography are the examination of choice, and the management is surgical.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/27248774?dopt=Abstract ER - TY - JOUR T1 - Genetic analysis of Italian patients with congenital tufting enteropathy. JF - World J Pediatr Y1 - 2015 A1 - d'Apolito, Maria A1 - Pisanelli, Daniela A1 - Faletra, Flavio A1 - Giardino, Ida A1 - Gigante, Maddalena A1 - Pettoello-Mantovani, Massimo A1 - Goulet, Olivier A1 - Gasparini, Paolo A1 - Campanozzi, Angelo AB -

BACKGROUND: Congenital tufting enteropathy (CTE), an inherited autosomal recessive rare disease, is a severe diarrhea of infancy which is clinically characterized by absence of inflammation and presence of intestinal villous atrophy. Mutations in the EpCAM gene were identified to cause CTE. Recent cases of syndromic tufting enteropathy harboring the SPINT2 (19q13.2) mutation were described.

METHODS: Four CTE Italian patients were clinically and immunohistochemically characterized. Direct DNA sequencing of EpCAM and SPINT2 genes was performed.

RESULTS: All patients were of Italian origin. Three different mutations were detected (p.Asp219Metfs*15, Tyr186Phefs*6 and p.Ile146Asn) in the EpCAM gene; one of them is novel (p.Ile146Asn). Two patients (P1 and P2) showed compound heterozygosity revealing two mutations in separate alleles. A third patient (P3) was heterozygous for only one novel EpCAM missense mutation (p.Ile146Asn). In a syndromic patient (P4), no deleterious EpCAM mutation was found. Additional SPINT2 mutational analysis was performed. P4 showed a homozygous SPINT2 mutation (p.Y163C). No SPINT2 mutation was found in P3. CLDN7 was also evaluated as a candidate gene by mutational screening in P3 but no mutation was identified.

CONCLUSIONS: This study presented a molecular characterization of CTE Italian patients, and identified three mutations in the EpCAM gene and one in the SPINT2 gene. One of EpCAM mutations was novel, therefore increasing the mutational spectrum of allelic variants of the EpCAM gene. Molecular analysis of the SPINT2 gene also allowed us to identify a SPINT2 substitution mutation (c.488A>G) recently found to be associated with syndromic CTE subjects.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/26684320?dopt=Abstract ER - TY - JOUR T1 - Genetic determinants for methotrexate response in juvenile idiopathic arthritis. JF - Front Pharmacol Y1 - 2015 A1 - Pastore, Serena A1 - Stocco, Gabriele A1 - Favretto, Diego A1 - De Iudicibus, Sara A1 - Taddio, Andrea A1 - d'Adamo, Pio A1 - Malusà, Noelia A1 - Addobbati, Riccardo A1 - Decorti, Giuliana A1 - Lepore, Loredana A1 - Ventura, Alessandro AB -

Juvenile idiopathic arthritis (JIAs) is the most common chronic rheumatic disease of childhood and is an important cause of disability. The folic acid analog methotrexate is the first choice disease-modifying anti-rheumatic drug in this disease, however, 35-45% of patients fail to respond. Molecular elements, such as variants in genes of pharmacological relevance, influencing response to methotrexate in JIA, would be important to individualize treatment strategies. Several studies have evaluated the effects of candidate genetic variants in the complex pathway of genes involved in methotrexate pharmacodynamics and pharmacokinetics, however, results are still contrasting and no definitive genetic marker of methotrexate response useful for the clinician to tailor therapy of children with JIA has been identified. Recently, genome-wide approaches have been applied, identifying new potential biological processes involved in methotrexate response in JIA such as TGF-beta signaling and calcium channels. If these genomic results are properly validated and integrated with innovative analyses comprising deep sequencing, epigenetics, and pharmacokinetics, they will greatly contribute to personalize therapy with methotrexate in children with JIA.

VL - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25852556?dopt=Abstract ER - TY - JOUR T1 - Genetic evidence for an origin of the Armenians from Bronze Age mixing of multiple populations. JF - Eur J Hum Genet Y1 - 2015 A1 - Haber, Marc A1 - Mezzavilla, Massimo A1 - Xue, Yali A1 - Comas, David A1 - Gasparini, Paolo A1 - Zalloua, Pierre A1 - Tyler-Smith, Chris AB -

The Armenians are a culturally isolated population who historically inhabited a region in the Near East bounded by the Mediterranean and Black seas and the Caucasus, but remain under-represented in genetic studies and have a complex history including a major geographic displacement during World War I. Here, we analyse genome-wide variation in 173 Armenians and compare them with 78 other worldwide populations. We find that Armenians form a distinctive cluster linking the Near East, Europe, and the Caucasus. We show that Armenian diversity can be explained by several mixtures of Eurasian populations that occurred between ~3000 and ~2000 bce, a period characterized by major population migrations after the domestication of the horse, appearance of chariots, and the rise of advanced civilizations in the Near East. However, genetic signals of population mixture cease after ~1200 bce when Bronze Age civilizations in the Eastern Mediterranean world suddenly and violently collapsed. Armenians have since remained isolated and genetic structure within the population developed ~500 years ago when Armenia was divided between the Ottomans and the Safavid Empire in Iran. Finally, we show that Armenians have higher genetic affinity to Neolithic Europeans than other present-day Near Easterners, and that 29% of Armenian ancestry may originate from an ancestral population that is best represented by Neolithic Europeans.European Journal of Human Genetics advance online publication, 21 October 2015; doi:10.1038/ejhg.2015.206.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/26486470?dopt=Abstract ER - TY - JOUR T1 - Genetic profiling of autoinflammatory disorders in patients with periodic fever: a prospective study. JF - Pediatr Rheumatol Online J Y1 - 2015 A1 - De Pieri, Carlo A1 - Vuch, Josef A1 - De Martino, Eleonora A1 - Bianco, Anna M A1 - Ronfani, Luca A1 - Athanasakis, Emmanouil A1 - Bortot, Barbara A1 - Crovella, Sergio A1 - Taddio, Andrea A1 - Severini, Giovanni M A1 - Tommasini, Alberto KW - Adolescent KW - Carrier Proteins KW - Child KW - Cryopyrin-Associated Periodic Syndromes KW - Cytoskeletal Proteins KW - Familial Mediterranean Fever KW - Female KW - Fever KW - Gene Expression Profiling KW - Genotype KW - Hereditary Autoinflammatory Diseases KW - Humans KW - Intracellular Signaling Peptides and Proteins KW - Logistic Models KW - Male KW - Mutation KW - Phosphotransferases (Alcohol Group Acceptor) KW - Prospective Studies KW - Receptors, Tumor Necrosis Factor, Type I KW - Syndrome AB -

BACKGROUND: Periodic fever syndromes (PFS) are an emerging group of autoinflammatory disorders. Clinical overlap exists and multiple genetic analyses may be needed to assist diagnosis. We evaluated the diagnostic value of a 5-gene sequencing panel (5GP) in patients with undiagnosed PFS.

METHODS: Simultaneous double strand Sanger sequencing of MEFV, MVK, TNFRSF1A, NLRP3, NLRP12 genes was performed in 42 patients with unexplained PFS. Clinical features were correlated with genetic results.

RESULTS: None of 42 patients analyzed displayed a causative genotype. However, single or multiple genetic variants of uncertain significance were detected in 24 subjects. Only in 5 subjects a definite diagnosis was made by taking into account both genetic and clinical data (2 TRAPS syndrome; 2 FMF; 1 FCAS). Statistical analysis showed that patients carrying genetic variants in one or more of the five selected genes displayed a significantly lower response to glucocorticoids compared with subjects who had completely negative genetic results.

CONCLUSIONS: The sequencing of multiple genes is of little help in the diagnostics of PFS and can often lead to results of uncertain interpretation, thus the clinically driven sequencing of single genes should remain the recommended approach. However, the presence of single or multiple genetic variants of uncertain significance, even if not allowing any specific diagnosis, correlated with a poorer response to glucocorticoids, possibly indicating a multifactorial subgroup of PFS with differential response to pharmacological treatment.

VL - 13 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25866490?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 - Genetic testing and genomic analysis: a debate on ethical, social and legal issues in the Arab world with a focus on Qatar. JF - J Transl Med Y1 - 2015 A1 - El Shanti, Hatem A1 - Chouchane, Lotfi A1 - Badii, Ramin A1 - Gallouzi, Imed Eddine A1 - Gasparini, Paolo AB -

In 2013 both Saudi Arabia and Qatar launched genome projects with the aim of providing information for better diagnosis, treatment and prevention of diseases and, ultimately to realize personalized medicine by sequencing hundred thousands samples. These population based genome activities raise a series of relevant ethical, legal and social issues general, related to the specific population structure as well as to the Islamic perspective on genomic analysis and genetic testing. To contribute to the debate, the Authors after reviewing the existing literature and taking advantage of their professional experience in the field and in the geographic area, discuss and provide their opinions. In particular, the Authors focus on the impact of consanguinity on population structure and disease frequency in the Arab world, on genetic testing and genomic analysis (i.e. technical aspects, impact, etc.) and on their regulations. A comparison between the Islamic perspective and the ethical, social and legal issues raised in other population contexts is also carried. In conclusion, this opinion article with an up-to-date contribution to the discussion on the relevance and impact of genomic analysis and genetic testing in the Arab world, might help in producing specific national guidelines on genetic testing and genomic analysis and help accelerate the implementation and roll out of genome projects in Muslim countries and more specifically in Qatar, and other countries of the Gulf.

VL - 13 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26572608?dopt=Abstract ER - TY - JOUR T1 - Genetics of inflammatory bowel disease from multifactorial to monogenic forms. JF - World J Gastroenterol Y1 - 2015 A1 - Bianco, Anna Monica A1 - Girardelli, Martina A1 - Tommasini, Alberto AB -

Inflammatory bowel disease (IBD) is a group of chronic multifactorial disorders. According to a recent study, the number of IBD association loci is increased to 201, of which 37 and 27 loci contribute specifically to the development of Crohn's disease and ulcerative colitis respectively. Some IBD associated genes are involved in innate immunity, in the autophagy and in the inflammatory response such as NOD2, ATG16L1 and IL23R, while other are implicated in immune mediated disease (STAT3) and in susceptibility to mycobacterium infection (IL12B). In case of early onset of IBD (VEO-IBD) within the 6(th) year of age, the disease may be caused by mutations in genes responsible for severe monogenic disorders such as the primary immunodeficiency diseases. In this review we discuss how these monogenic disorders through different immune mechanisms can similarly be responsible of VEO-IBD phenotype. Moreover we would highlight how the identification of pathogenic genes by Next Generation Sequencing technologies can allow to obtain a rapid diagnosis and to apply specific therapies.

VL - 21 IS - 43 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26604638?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 - Genome-wide association analysis on normal hearing function identifies PCDH20 and SLC28A3 as candidates for hearing function and loss. JF - Hum Mol Genet Y1 - 2015 A1 - Vuckovic, Dragana A1 - Dawson, Sally A1 - Scheffer, Deborah I A1 - Rantanen, Taina A1 - Morgan, Anna A1 - Di Stazio, Mariateresa A1 - Vozzi, Diego A1 - Nutile, Teresa A1 - Concas, Maria P A1 - Biino, Ginevra A1 - Nolan, Lisa A1 - Bahl, Aileen A1 - Loukola, Anu A1 - Viljanen, Anne A1 - Davis, Adrian A1 - Ciullo, Marina A1 - Corey, David P A1 - Pirastu, Mario A1 - Gasparini, Paolo A1 - Girotto, Giorgia AB -

Hearing loss and individual differences in normal hearing both have a substantial genetic basis. Although many new genes contributing to deafness have been identified, very little is known about genes/variants modulating the normal range of hearing ability. To fill this gap, we performed a two-stage meta-analysis on hearing thresholds (tested at 0.25, 0.5, 1, 2, 4, 8 kHz) and on pure-tone averages (low-, medium- and high-frequency thresholds grouped) in several isolated populations from Italy and Central Asia (total N = 2636). Here, we detected two genome-wide significant loci close to PCDH20 and SLC28A3 (top hits: rs78043697, P = 4.71E-10 and rs7032430, P = 2.39E-09, respectively). For both loci, we sought replication in two independent cohorts: B58C from the UK (N = 5892) and FITSA from Finland (N = 270). Both loci were successfully replicated at a nominal level of significance (P < 0.05). In order to confirm our quantitative findings, we carried out RT-PCR and reported RNA-Seq data, which showed that both genes are expressed in mouse inner ear, especially in hair cells, further suggesting them as good candidates for modulatory genes in the auditory system. Sequencing data revealed no functional variants in the coding region of PCDH20 or SLC28A3, suggesting that variation in regulatory sequences may affect expression. Overall, these results contribute to a better understanding of the complex mechanisms underlying human hearing function.

VL - 24 IS - 19 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26188009?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 age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. JF - Lancet Y1 - 2015 KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Cause of Death KW - Child KW - Child Mortality KW - Child, Preschool KW - Databases, Factual KW - Female KW - Global Health KW - Humans KW - Infant KW - Infant, Newborn KW - Life Expectancy KW - Life Tables KW - Male KW - Middle Aged KW - Models, Statistical KW - Mortality KW - Sex Distribution KW - Young Adult AB -

BACKGROUND: Up-to-date evidence on levels and trends for age-sex-specific all-cause and cause-specific mortality is essential for the formation of global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013) we estimated yearly deaths for 188 countries between 1990, and 2013. We used the results to assess whether there is epidemiological convergence across countries.

METHODS: We estimated age-sex-specific all-cause mortality using the GBD 2010 methods with some refinements to improve accuracy applied to an updated database of vital registration, survey, and census data. We generally estimated cause of death as in the GBD 2010. Key improvements included the addition of more recent vital registration data for 72 countries, an updated verbal autopsy literature review, two new and detailed data systems for China, and more detail for Mexico, UK, Turkey, and Russia. We improved statistical models for garbage code redistribution. We used six different modelling strategies across the 240 causes; cause of death ensemble modelling (CODEm) was the dominant strategy for causes with sufficient information. Trends for Alzheimer's disease and other dementias were informed by meta-regression of prevalence studies. For pathogen-specific causes of diarrhoea and lower respiratory infections we used a counterfactual approach. We computed two measures of convergence (inequality) across countries: the average relative difference across all pairs of countries (Gini coefficient) and the average absolute difference across countries. To summarise broad findings, we used multiple decrement life-tables to decompose probabilities of death from birth to exact age 15 years, from exact age 15 years to exact age 50 years, and from exact age 50 years to exact age 75 years, and life expectancy at birth into major causes. For all quantities reported, we computed 95% uncertainty intervals (UIs). We constrained cause-specific fractions within each age-sex-country-year group to sum to all-cause mortality based on draws from the uncertainty distributions.

FINDINGS: Global life expectancy for both sexes increased from 65.3 years (UI 65.0-65.6) in 1990, to 71.5 years (UI 71.0-71.9) in 2013, while the number of deaths increased from 47.5 million (UI 46.8-48.2) to 54.9 million (UI 53.6-56.3) over the same interval. Global progress masked variation by age and sex: for children, average absolute differences between countries decreased but relative differences increased. For women aged 25-39 years and older than 75 years and for men aged 20-49 years and 65 years and older, both absolute and relative differences increased. Decomposition of global and regional life expectancy showed the prominent role of reductions in age-standardised death rates for cardiovascular diseases and cancers in high-income regions, and reductions in child deaths from diarrhoea, lower respiratory infections, and neonatal causes in low-income regions. HIV/AIDS reduced life expectancy in southern sub-Saharan Africa. For most communicable causes of death both numbers of deaths and age-standardised death rates fell whereas for most non-communicable causes, demographic shifts have increased numbers of deaths but decreased age-standardised death rates. Global deaths from injury increased by 10.7%, from 4.3 million deaths in 1990 to 4.8 million in 2013; but age-standardised rates declined over the same period by 21%. For some causes of more than 100,000 deaths per year in 2013, age-standardised death rates increased between 1990 and 2013, including HIV/AIDS, pancreatic cancer, atrial fibrillation and flutter, drug use disorders, diabetes, chronic kidney disease, and sickle-cell anaemias. Diarrhoeal diseases, lower respiratory infections, neonatal causes, and malaria are still in the top five causes of death in children younger than 5 years. The most important pathogens are rotavirus for diarrhoea and pneumococcus for lower respiratory infections. Country-specific probabilities of death over three phases of life were substantially varied between and within regions.

INTERPRETATION: For most countries, the general pattern of reductions in age-sex specific mortality has been associated with a progressive shift towards a larger share of the remaining deaths caused by non-communicable disease and injuries. Assessing epidemiological convergence across countries depends on whether an absolute or relative measure of inequality is used. Nevertheless, age-standardised death rates for seven substantial causes are increasing, suggesting the potential for reversals in some countries. Important gaps exist in the empirical data for cause of death estimates for some countries; for example, no national data for India are available for the past decade.

FUNDING: Bill & Melinda Gates Foundation.

VL - 385 IS - 9963 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25530442?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 - Caravanos, Jack A1 - Cárdenas, Rosario A1 - Cardis, Elisabeth 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 - Chen, Zhengming A1 - Chiang, Peggy P A1 - Chimed-Ochir, Odgerel A1 - Chowdhury, Rajiv A1 - Christophi, Costas A A1 - Chuang, Ting-Wu A1 - Chugh, Sumeet S A1 - Cirillo, Massimo A1 - Claßen, Thomas K D A1 - Colistro, Valentina A1 - Colomar, Mercedes A1 - Colquhoun, Samantha M A1 - Contreras, Alejandra G A1 - Cooper, Cyrus A1 - Cooperrider, Kimberly A1 - Cooper, Leslie T A1 - Coresh, Josef A1 - Courville, Karen J A1 - Criqui, Michael H A1 - Cuevas-Nasu, Lucia A1 - Damsere-Derry, James A1 - Danawi, Hadi A1 - Dandona, Lalit A1 - Dandona, Rakhi A1 - Dargan, Paul I A1 - Davis, Adrian A1 - Davitoiu, Dragos V A1 - Dayama, Anand A1 - de Castro, E Filipa A1 - De la Cruz-Góngora, Vanessa A1 - De Leo, Diego A1 - de Lima, Graça 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 - deVeber, Gabrielle A A1 - Devries, Karen M A1 - Dharmaratne, Samath D A1 - Dherani, Mukesh K A1 - Dicker, Daniel A1 - Ding, Eric L A1 - Dokova, Klara A1 - Dorsey, E Ray A1 - Driscoll, Tim R A1 - Duan, Leilei A1 - Durrani, Adnan M A1 - Ebel, Beth E A1 - Ellenbogen, Richard G A1 - Elshrek, Yousef M A1 - Endres, Matthias A1 - Ermakov, Sergey P A1 - Erskine, Holly E A1 - Eshrati, Babak A1 - Esteghamati, Alireza A1 - Fahimi, Saman A1 - Faraon, Emerito Jose A A1 - Farzadfar, Farshad A1 - Fay, Derek F J A1 - Feigin, Valery L A1 - Feigl, Andrea B A1 - Fereshtehnejad, Seyed-Mohammad A1 - Ferrari, Alize J A1 - Ferri, Cleusa P A1 - Flaxman, Abraham D A1 - Fleming, Thomas D A1 - Foigt, Nataliya A1 - Foreman, Kyle J A1 - Paleo, Urbano Fra A1 - Franklin, Richard C A1 - Gabbe, Belinda A1 - Gaffikin, Lynne A1 - Gakidou, Emmanuela A1 - Gamkrelidze, Amiran A1 - Gankpé, Fortuné G A1 - Gansevoort, Ron T A1 - García-Guerra, Francisco A A1 - Gasana, Evariste A1 - Geleijnse, Johanna M A1 - Gessner, Bradford D A1 - Gething, Pete A1 - Gibney, Katherine B A1 - Gillum, Richard F A1 - Ginawi, Ibrahim A M A1 - Giroud, Maurice A1 - Giussani, Giorgia A1 - Goenka, Shifalika A1 - Goginashvili, Ketevan A1 - Gomez Dantes, Hector A1 - Gona, Philimon A1 - Gonzalez de Cosio, Teresita A1 - González-Castell, Dinorah A1 - Gotay, Carolyn C A1 - Goto, Atsushi A1 - Gouda, Hebe N A1 - Guerrant, Richard L A1 - Gugnani, Harish C A1 - Guillemin, Francis A1 - Gunnell, David A1 - Gupta, Rahul A1 - Gupta, Rajeev A1 - Gutiérrez, Reyna A A1 - Hafezi-Nejad, Nima A1 - Hagan, Holly A1 - Hagstromer, Maria A1 - Halasa, Yara A A1 - Hamadeh, Randah R A1 - Hammami, Mouhanad A1 - Hankey, Graeme J A1 - Hao, Yuantao A1 - Harb, Hilda L A1 - Haregu, Tilahun Nigatu A1 - Haro, Josep Maria A1 - Havmoeller, Rasmus A1 - Hay, Simon I A1 - Hedayati, Mohammad T A1 - Heredia-Pi, Ileana B A1 - Hernandez, Lucia A1 - Heuton, Kyle R A1 - Heydarpour, Pouria A1 - Hijar, Martha A1 - Hoek, Hans W A1 - Hoffman, Howard J A1 - Hornberger, John C A1 - Hosgood, H Dean A1 - Hoy, Damian G A1 - Hsairi, Mohamed A1 - Hu, Guoqing A1 - Hu, Howard A1 - Huang, Cheng A1 - Huang, John J A1 - Hubbell, Bryan J A1 - Huiart, Laetitia A1 - Husseini, Abdullatif A1 - Iannarone, Marissa L A1 - Iburg, Kim M A1 - Idrisov, Bulat T A1 - Ikeda, Nayu A1 - Innos, Kaire A1 - Inoue, Manami A1 - Islami, Farhad A1 - Ismayilova, Samaya A1 - Jacobsen, Kathryn H A1 - Jansen, Henrica A A1 - Jarvis, Deborah L A1 - Jassal, Simerjot K A1 - Jauregui, Alejandra A1 - Jayaraman, Sudha A1 - Jeemon, Panniyammakal A1 - Jensen, Paul N A1 - Jha, Vivekanand A1 - Jiang, Fan A1 - Jiang, Guohong A1 - Jiang, Ying A1 - Jonas, Jost B A1 - Juel, Knud A1 - Kan, Haidong A1 - Kany Roseline, Sidibe S A1 - Karam, Nadim E A1 - Karch, André A1 - Karema, Corine K A1 - Karthikeyan, Ganesan A1 - Kaul, Anil A1 - Kawakami, Norito A1 - Kazi, Dhruv S A1 - Kemp, Andrew H A1 - Kengne, Andre P A1 - Keren, Andre A1 - Khader, Yousef S A1 - Khalifa, Shams Eldin Ali Hassan A1 - Khan, Ejaz A A1 - Khang, Young-Ho A1 - Khatibzadeh, Shahab A1 - Khonelidze, Irma A1 - Kieling, Christian A1 - Kim, Daniel A1 - Kim, Sungroul A1 - Kim, Yunjin A1 - Kimokoti, Ruth W A1 - Kinfu, Yohannes A1 - Kinge, Jonas M A1 - Kissela, Brett M A1 - Kivipelto, Miia A1 - Knibbs, Luke D A1 - Knudsen, Ann Kristin A1 - Kokubo, Yoshihiro A1 - Kose, M Rifat A1 - Kosen, Soewarta A1 - Kraemer, Alexander A1 - Kravchenko, Michael A1 - Krishnaswami, Sanjay A1 - Kromhout, Hans A1 - Ku, Tiffany A1 - Kuate Defo, Barthelemy A1 - Kucuk Bicer, Burcu A1 - Kuipers, Ernst J A1 - Kulkarni, Chanda A1 - Kulkarni, Veena S A1 - Kumar, G Anil A1 - Kwan, Gene F A1 - Lai, Taavi A1 - Lakshmana Balaji, Arjun A1 - Lalloo, Ratilal A1 - Lallukka, Tea A1 - Lam, Hilton A1 - Lan, Qing A1 - Lansingh, Van C A1 - Larson, Heidi J A1 - Larsson, Anders A1 - Laryea, Dennis O A1 - Lavados, Pablo M A1 - Lawrynowicz, Alicia E A1 - Leasher, Janet L A1 - Lee, Jong-Tae A1 - Leigh, James A1 - Leung, Ricky A1 - Levi, Miriam A1 - Li, Yichong A1 - Li, Yongmei A1 - Liang, Juan A1 - Liang, Xiaofeng A1 - Lim, Stephen S A1 - Lindsay, M Patrice A1 - Lipshultz, Steven E A1 - Liu, Shiwei A1 - Liu, Yang A1 - Lloyd, Belinda K A1 - Logroscino, Giancarlo A1 - London, Stephanie J A1 - Lopez, Nancy A1 - Lortet-Tieulent, Joannie A1 - Lotufo, Paulo A A1 - Lozano, Rafael A1 - Lunevicius, Raimundas A1 - Ma, Jixiang A1 - Ma, Stefan A1 - Machado, Vasco M P A1 - MacIntyre, Michael F A1 - Magis-Rodriguez, Carlos A1 - Mahdi, Abbas A A1 - Majdan, Marek A1 - Malekzadeh, Reza A1 - Mangalam, Srikanth A1 - Mapoma, Christopher C A1 - Marape, Marape A1 - Marcenes, Wagner A1 - Margolis, David J A1 - Margono, Christopher A1 - Marks, Guy B A1 - Martin, Randall V A1 - Marzan, Melvin B A1 - Mashal, Mohammad T A1 - Masiye, Felix A1 - Mason-Jones, Amanda J A1 - Matsushita, Kunihiro A1 - Matzopoulos, Richard A1 - Mayosi, Bongani M A1 - Mazorodze, Tasara T A1 - McKay, Abigail C A1 - McKee, Martin A1 - McLain, Abigail A1 - Meaney, Peter A A1 - Medina, Catalina A1 - Mehndiratta, Man Mohan A1 - Mejia-Rodriguez, Fabiola A1 - Mekonnen, Wubegzier A1 - Melaku, Yohannes A A1 - Meltzer, Michele A1 - Memish, Ziad A A1 - Mendoza, Walter A1 - Mensah, George A A1 - Meretoja, Atte A1 - Mhimbira, Francis Apolinary A1 - Micha, Renata A1 - Miller, Ted R A1 - Mills, Edward J A1 - Misganaw, Awoke A1 - Mishra, Santosh A1 - Mohamed Ibrahim, Norlinah A1 - Mohammad, Karzan A A1 - Mokdad, Ali H A1 - Mola, Glen L A1 - Monasta, Lorenzo A1 - Montañez Hernandez, Julio C A1 - Montico, Marcella A1 - Moore, Ami R A1 - Morawska, Lidia A1 - Mori, Rintaro A1 - Moschandreas, Joanna A1 - Moturi, Wilkister N A1 - Mozaffarian, Dariush A1 - Mueller, Ulrich O A1 - Mukaigawara, Mitsuru A1 - Mullany, Erin C A1 - Murthy, Kinnari S A1 - Naghavi, Mohsen A1 - Nahas, Ziad A1 - Naheed, Aliya A1 - Naidoo, Kovin S A1 - Naldi, Luigi A1 - Nand, Devina A1 - Nangia, Vinay A1 - Narayan, K M Venkat A1 - Nash, Denis A1 - Neal, Bruce A1 - Nejjari, Chakib A1 - Neupane, Sudan P A1 - Newton, Charles R A1 - Ngalesoni, Frida N A1 - Ngirabega, Jean de Dieu A1 - Nguyen, Grant A1 - Nguyen, Nhung T A1 - Nieuwenhuijsen, Mark J A1 - Nisar, Muhammad I A1 - Nogueira, José R A1 - Nolla, Joan M 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 - Olusanya, Bolajoko O A1 - Omer, Saad B A1 - Opio, John Nelson A1 - Orozco, Ricardo A1 - Pagcatipunan, Rodolfo S A1 - Pain, Amanda W A1 - Pandian, Jeyaraj D A1 - Panelo, Carlo Irwin A A1 - Papachristou, Christina A1 - Park, Eun-Kee A1 - Parry, Charles D A1 - Paternina Caicedo, Angel J A1 - Patten, Scott B A1 - Paul, Vinod K A1 - Pavlin, Boris I A1 - Pearce, Neil A1 - Pedraza, Lilia S A1 - Pedroza, Andrea A1 - Pejin Stokic, Ljiljana A1 - Pekericli, Ayfer A1 - Pereira, David M A1 - Perez-Padilla, Rogelio A1 - Perez-Ruiz, Fernando A1 - Perico, Norberto A1 - Perry, Samuel A L A1 - Pervaiz, Aslam A1 - Pesudovs, Konrad A1 - Peterson, Carrie B A1 - Petzold, Max A1 - Phillips, Michael R A1 - Phua, Hwee Pin A1 - Plass, Dietrich A1 - Poenaru, Dan A1 - Polanczyk, Guilherme V A1 - Polinder, Suzanne A1 - Pond, Constance D A1 - Pope, C Arden A1 - Pope, Daniel A1 - Popova, Svetlana A1 - Pourmalek, Farshad A1 - Powles, John A1 - Prabhakaran, Dorairaj A1 - Prasad, Noela M A1 - Qato, Dima M A1 - Quezada, Amado D A1 - Quistberg, D Alex A A1 - Racapé, Lionel A1 - Rafay, Anwar A1 - Rahimi, Kazem A1 - Rahimi-Movaghar, Vafa A1 - Rahman, Sajjad Ur A1 - Raju, Murugesan A1 - Rakovac, Ivo A1 - Rana, Saleem M A1 - Rao, Mayuree A1 - Razavi, Homie A1 - Reddy, K Srinath A1 - Refaat, Amany H A1 - Rehm, Jürgen A1 - Remuzzi, Giuseppe A1 - Ribeiro, Antonio L A1 - Riccio, Patricia M A1 - Richardson, Lee A1 - Riederer, Anne A1 - Robinson, Margaret A1 - Roca, Anna A1 - Rodriguez, Alina A1 - Rojas-Rueda, David A1 - Romieu, Isabelle A1 - Ronfani, Luca A1 - Room, Robin A1 - Roy, Nobhojit A1 - Ruhago, George M A1 - Rushton, Lesley A1 - Sabin, Nsanzimana A1 - Sacco, Ralph L A1 - Saha, Sukanta A1 - Sahathevan, Ramesh A1 - Sahraian, Mohammad Ali A1 - Salomon, Joshua A A1 - Salvo, Deborah A1 - Sampson, Uchechukwu K A1 - Sanabria, Juan R A1 - Sanchez, Luz Maria A1 - Sánchez-Pimienta, Tania G A1 - Sanchez-Riera, Lidia A1 - Sandar, Logan A1 - Santos, Itamar S A1 - Sapkota, Amir A1 - Satpathy, Maheswar A1 - Saunders, James E A1 - Sawhney, Monika A1 - Saylan, Mete I A1 - Scarborough, Peter A1 - Schmidt, Jürgen C A1 - Schneider, Ione J C A1 - Schöttker, Ben A1 - Schwebel, David C A1 - Scott, James G A1 - Seedat, Soraya A1 - Sepanlou, Sadaf G A1 - Serdar, Berrin A1 - Servan-Mori, Edson E A1 - Shaddick, Gavin A1 - Shahraz, Saeid A1 - Levy, Teresa Shamah A1 - Shangguan, Siyi A1 - She, Jun A1 - Sheikhbahaei, Sara A1 - Shibuya, Kenji A1 - Shin, Hwashin H A1 - Shinohara, Yukito A1 - Shiri, Rahman A1 - Shishani, Kawkab A1 - Shiue, Ivy A1 - Sigfusdottir, Inga D A1 - Silberberg, Donald H A1 - Simard, Edgar P A1 - Sindi, Shireen A1 - Singh, Abhishek A1 - Singh, Gitanjali M A1 - Singh, Jasvinder A A1 - Skirbekk, Vegard A1 - Sliwa, Karen A1 - Soljak, Michael A1 - Soneji, Samir A1 - Søreide, Kjetil A1 - Soshnikov, Sergey A1 - Sposato, Luciano A A1 - Sreeramareddy, Chandrashekhar T A1 - Stapelberg, Nicolas J C A1 - Stathopoulou, Vasiliki A1 - Steckling, Nadine A1 - Stein, Dan J A1 - Stein, Murray B A1 - Stephens, Natalie A1 - Stöckl, Heidi A1 - Straif, Kurt A1 - Stroumpoulis, Konstantinos A1 - Sturua, Lela A1 - Sunguya, Bruno F A1 - Swaminathan, Soumya A1 - Swaroop, Mamta A1 - Sykes, Bryan L A1 - Tabb, Karen M A1 - Takahashi, Ken A1 - Talongwa, Roberto T A1 - Tandon, Nikhil A1 - Tanne, David A1 - Tanner, Marcel A1 - Tavakkoli, Mohammad A1 - Te Ao, Braden J A1 - Teixeira, Carolina M A1 - Téllez Rojo, Martha M A1 - Terkawi, Abdullah S A1 - Texcalac-Sangrador, José Luis A1 - Thackway, Sarah V A1 - Thomson, Blake A1 - Thorne-Lyman, Andrew L A1 - Thrift, Amanda G A1 - Thurston, George D A1 - Tillmann, Taavi A1 - Tobollik, Myriam A1 - Tonelli, Marcello A1 - Topouzis, Fotis A1 - Towbin, Jeffrey A A1 - Toyoshima, Hideaki A1 - Traebert, Jefferson A1 - Tran, Bach X A1 - Trasande, Leonardo A1 - Trillini, Matias A1 - Trujillo, Ulises A1 - Dimbuene, Zacharie Tsala A1 - Tsilimbaris, Miltiadis A1 - Tuzcu, Emin Murat A1 - Uchendu, Uche S A1 - Ukwaja, Kingsley N A1 - Uzun, Selen B A1 - van de Vijver, Steven A1 - Van Dingenen, Rita A1 - van Gool, Coen H A1 - van Os, Jim A1 - Varakin, Yuri Y A1 - Vasankari, Tommi J A1 - Vasconcelos, Ana Maria N A1 - Vavilala, Monica S A1 - Veerman, Lennert J A1 - Velasquez-Melendez, Gustavo A1 - Venketasubramanian, N A1 - Vijayakumar, Lakshmi A1 - Villalpando, Salvador A1 - Violante, Francesco S A1 - Vlassov, Vasiliy Victorovich A1 - Vollset, Stein Emil A1 - Wagner, Gregory R A1 - Waller, Stephen G A1 - Wallin, Mitchell T A1 - Wan, Xia A1 - Wang, Haidong A1 - Wang, JianLi A1 - Wang, Linhong A1 - Wang, Wenzhi A1 - Wang, Yanping A1 - Warouw, Tati S A1 - Watts, Charlotte H A1 - Weichenthal, Scott A1 - Weiderpass, Elisabete A1 - Weintraub, Robert G A1 - Werdecker, Andrea A1 - Wessells, K Ryan A1 - Westerman, Ronny A1 - Whiteford, Harvey A A1 - Wilkinson, James D A1 - Williams, Hywel C A1 - Williams, Thomas N A1 - Woldeyohannes, Solomon M A1 - Wolfe, Charles D A A1 - Wong, John Q A1 - Woolf, Anthony D A1 - Wright, Jonathan L A1 - Wurtz, Brittany A1 - Xu, Gelin A1 - Yan, Lijing L A1 - Yang, Gonghuan A1 - Yano, Yuichiro A1 - Ye, Pengpeng A1 - Yenesew, Muluken A1 - Yentür, Gökalp K A1 - Yip, Paul A1 - Yonemoto, Naohiro A1 - Yoon, Seok-Jun A1 - Younis, Mustafa Z A1 - Younoussi, Zourkaleini A1 - Yu, Chuanhua A1 - Zaki, Maysaa E A1 - Zhao, Yong A1 - Zheng, Yingfeng A1 - Zhou, Maigeng A1 - Zhu, Jun A1 - Zhu, Shankuan A1 - Zou, Xiaonong A1 - Zunt, Joseph R A1 - Lopez, Alan D A1 - Vos, Theo A1 - Murray, Christopher J AB -

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 - Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. JF - Lancet Y1 - 2015 KW - Acute Disease KW - Adolescent KW - Adult KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Child KW - Child, Preschool KW - Chronic Disease KW - Cost of Illness KW - Developed Countries KW - Developing Countries KW - Disabled Persons KW - Female KW - Global Health KW - Humans KW - Incidence KW - Infant KW - Infant, Newborn KW - Male KW - Middle Aged KW - Neglected Diseases KW - Prevalence KW - Residence Characteristics KW - Sex Distribution KW - Wounds and Injuries KW - Young Adult AB -

BACKGROUND: Up-to-date evidence about levels and trends in disease and injury incidence, prevalence, and years lived with disability (YLDs) is an essential input into global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013), we estimated these quantities for acute and chronic diseases and injuries for 188 countries between 1990 and 2013.

METHODS: Estimates were calculated for disease and injury incidence, prevalence, and YLDs using GBD 2010 methods with some important refinements. Results for incidence of acute disorders and prevalence of chronic disorders are new additions to the analysis. Key improvements include expansion to the cause and sequelae list, updated systematic reviews, use of detailed injury codes, improvements to the Bayesian meta-regression method (DisMod-MR), and use of severity splits for various causes. An index of data representativeness, showing data availability, was calculated for each cause and impairment during three periods globally and at the country level for 2013. In total, 35 620 distinct sources of data were used and documented to calculated estimates for 301 diseases and injuries and 2337 sequelae. The comorbidity simulation provides estimates for the number of sequelae, concurrently, by individuals by country, year, age, and sex. Disability weights were updated with the addition of new population-based survey data from four countries.

FINDINGS: Disease and injury were highly prevalent; only a small fraction of individuals had no sequelae. Comorbidity rose substantially with age and in absolute terms from 1990 to 2013. Incidence of acute sequelae were predominantly infectious diseases and short-term injuries, with over 2 billion cases of upper respiratory infections and diarrhoeal disease episodes in 2013, with the notable exception of tooth pain due to permanent caries with more than 200 million incident cases in 2013. Conversely, leading chronic sequelae were largely attributable to non-communicable diseases, with prevalence estimates for asymptomatic permanent caries and tension-type headache of 2·4 billion and 1·6 billion, respectively. The distribution of the number of sequelae in populations varied widely across regions, with an expected relation between age and disease prevalence. YLDs for both sexes increased from 537·6 million in 1990 to 764·8 million in 2013 due to population growth and ageing, whereas the age-standardised rate decreased little from 114·87 per 1000 people to 110·31 per 1000 people between 1990 and 2013. Leading causes of YLDs included low back pain and major depressive disorder among the top ten causes of YLDs in every country. YLD rates per person, by major cause groups, indicated the main drivers of increases were due to musculoskeletal, mental, and substance use disorders, neurological disorders, and chronic respiratory diseases; however HIV/AIDS was a notable driver of increasing YLDs in sub-Saharan Africa. Also, the proportion of disability-adjusted life years due to YLDs increased globally from 21·1% in 1990 to 31·2% in 2013.

INTERPRETATION: Ageing of the world's population is leading to a substantial increase in the numbers of individuals with sequelae of diseases and injuries. Rates of YLDs are declining much more slowly than mortality rates. The non-fatal dimensions of disease and injury will require more and more attention from health systems. The transition to non-fatal outcomes as the dominant source of burden of disease is occurring rapidly outside of sub-Saharan Africa. Our results can guide future health initiatives through examination of epidemiological trends and a better understanding of variation across countries.

FUNDING: Bill & Melinda Gates Foundation.

VL - 386 IS - 9995 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26063472?dopt=Abstract ER - TY - JOUR T1 - Glucocorticoid pharmacogenetics in pediatric idiopathic nephrotic syndrome. JF - Pharmacogenomics Y1 - 2015 A1 - Cuzzoni, Eva A1 - De Iudicibus, Sara A1 - Franca, Raffaella A1 - Stocco, Gabriele A1 - Lucafò, Marianna A1 - Pelin, Marco A1 - Favretto, Diego A1 - Pasini, Andrea A1 - Montini, Giovanni A1 - Decorti, Giuliana AB -

Idiopathic nephrotic syndrome represents the most common type of primary glomerular disease in children: glucocorticoids (GCs) are the first-line therapy, even if considerable interindividual differences in thepir efficacy and side effects have been reported. Immunosuppressive and anti-inflammatory effects of these drugs are mainly due to the GC-mediated transcription regulation of pro- and anti-inflammatory genes. This mechanism of action is the result of a complex multistep pathway that involves the glucocorticoid receptor and several other proteins, encoded by polymorphic genes. Aim of this review is to highlight the current knowledge on genetic variants that could affect GC response, particularly focusing on children with idiopathic nephrotic syndrome.

VL - 16 IS - 14 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26419298?dopt=Abstract ER - TY - JOUR T1 - GRID2 a novel gene possibly associated with mevalonate kinase deficiency. JF - Rheumatol Int Y1 - 2015 A1 - Moura, Ronald A1 - Tricarico, Paola Maura A1 - Campos Coelho, Antonio Victor A1 - Crovella, Sergio AB -

Mevalonate kinase deficiency (MKD) is a rare autosomal disease caused by mutations in the mevalonate kinase gene (MVK). The genotype-phenotype correlation is sometimes problematic due to the great genetic and clinical heterogeneity; so we hypothesize that genes other than MVK are able to modulate MKD clinical phenotypes. This hypothesis was tested by analyzing the exome of 22 patients with MKD all carrying MVK gene mutations, and 20 patients with recurrent fevers (RF) not carrying MVK mutations. Our preliminary findings suggest a possible role of GRID2 in the susceptibility to develop MKD. GRID2 gene (4q22.2), encoding for human glutamate receptor delta-2, associated with MKD: The rs1450500 SNP was differently distributed in patients with MKD with respect to those with RF. Being aware of the small number of patients analyzed, we hypothesized a possible role for GRID2 as possible phenotype modifier in MKD patients, especially in those with severe phenotypes.

VL - 35 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25146332?dopt=Abstract ER - TY - JOUR T1 - A general approach for haplotype phasing across the full spectrum of relatedness. JF - PLoS Genet Y1 - 2014 A1 - O'Connell, Jared A1 - Gurdasani, Deepti A1 - Delaneau, Olivier A1 - Pirastu, Nicola A1 - Ulivi, Sheila A1 - Cocca, Massimiliano A1 - Traglia, Michela A1 - Huang, Jie A1 - Huffman, Jennifer E A1 - Rudan, Igor A1 - McQuillan, Ruth A1 - Fraser, Ross M A1 - Campbell, Harry A1 - Polasek, Ozren A1 - Asiki, Gershim A1 - Ekoru, Kenneth A1 - Hayward, Caroline A1 - Wright, Alan F A1 - Vitart, Veronique A1 - Navarro, Pau A1 - Zagury, Jean-Francois A1 - Wilson, James F A1 - Toniolo, Daniela A1 - Gasparini, Paolo A1 - Soranzo, Nicole A1 - Sandhu, Manjinder S A1 - Marchini, Jonathan KW - Chromosome Mapping KW - Cohort Effect KW - Family KW - Genotype KW - Haplotypes KW - Humans KW - Models, Genetic KW - Pedigree KW - Phenotype KW - Recombination, Genetic AB -

Many existing cohorts contain a range of relatedness between genotyped individuals, either by design or by chance. Haplotype estimation in such cohorts is a central step in many downstream analyses. Using genotypes from six cohorts from isolated populations and two cohorts from non-isolated populations, we have investigated the performance of different phasing methods designed for nominally 'unrelated' individuals. We find that SHAPEIT2 produces much lower switch error rates in all cohorts compared to other methods, including those designed specifically for isolated populations. In particular, when large amounts of IBD sharing is present, SHAPEIT2 infers close to perfect haplotypes. Based on these results we have developed a general strategy for phasing cohorts with any level of implicit or explicit relatedness between individuals. First SHAPEIT2 is run ignoring all explicit family information. We then apply a novel HMM method (duoHMM) to combine the SHAPEIT2 haplotypes with any family information to infer the inheritance pattern of each meiosis at all sites across each chromosome. This allows the correction of switch errors, detection of recombination events and genotyping errors. We show that the method detects numbers of recombination events that align very well with expectations based on genetic maps, and that it infers far fewer spurious recombination events than Merlin. The method can also detect genotyping errors and infer recombination events in otherwise uninformative families, such as trios and duos. The detected recombination events can be used in association scans for recombination phenotypes. The method provides a simple and unified approach to haplotype estimation, that will be of interest to researchers in the fields of human, animal and plant genetics.

VL - 10 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24743097?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 - Genetic landscape of populations along the Silk Road: admixture and migration patterns. JF - BMC Genet Y1 - 2014 A1 - Mezzavilla, Massimo A1 - Vozzi, Diego A1 - Pirastu, Nicola A1 - Girotto, Giorgia A1 - d'Adamo, Pio A1 - Gasparini, Paolo A1 - Colonna, Vincenza KW - Asian Continental Ancestry Group KW - Commonwealth of Independent States KW - European Continental Ancestry Group KW - Gene Flow KW - Homozygote KW - Human Migration KW - Humans KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Principal Component Analysis KW - Sequence Analysis, DNA AB -

BACKGROUND: The ancient Silk Road has been a trading route between Europe and Central Asia from the 2(nd) century BCE to the 15(th) century CE. While most populations on this route have been characterized, the genetic background of others remains poorly understood, and little is known about past migration patterns. The scientific expedition "Marco Polo" has recently collected genetic and phenotypic data in six regions (Georgia, Armenia, Azerbaijan, Uzbekistan, Kazakhstan, Tajikistan) along the Silk Road to study the genetics of a number of phenotypes.

RESULTS: We characterized the genetic structure of these populations within a worldwide context. We observed a West-East subdivision albeit the existence of a genetic component shared within Central Asia and nearby populations from Europe and Near East. We observed a contribution of up to 50% from Europe and Asia to most of the populations that have been analyzed. The contribution from Asia dates back to ~25 generations and is limited to the Eastern Silk Road. Time and direction of this contribution are consistent with the Mongolian expansion era.

CONCLUSIONS: We clarified the genetic structure of six populations from Central Asia and suggested a complex pattern of gene flow among them. We provided a map of migration events in time and space and we quantified exchanges among populations. Altogether these novel findings will support the future studies aimed at understanding the genetics of the phenotypes that have been collected during the Marco Polo campaign, they will provide insights into the history of these populations, and they will be useful to reconstruct the developments and events that have shaped modern Eurasians genomes.

VL - 15 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25476266?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 - A girl with photosensitivity and hepatic steatosis. JF - J Pediatr Y1 - 2014 A1 - Pavan, Matteo A1 - Gortani, Giulia A1 - Rubinato, Elisa A1 - Faletra, Flavio A1 - Pastore, Serena A1 - Ventura, Alessandro KW - Child KW - Diagnosis, Differential KW - Fatty Liver KW - Female KW - Humans KW - Photosensitivity Disorders KW - Protoporphyria, Erythropoietic VL - 165 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24704299?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 - 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 - Genetics of food preferences: a first view from silk road populations. JF - J Food Sci Y1 - 2012 A1 - Pirastu, Nicola A1 - Robino, Antonietta A1 - Lanzara, Carmela A1 - Athanasakis, Emmanouil A1 - Esposito, Laura A1 - Tepper, Beverly J A1 - Gasparini, Paolo KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Azerbaijan KW - Child KW - Choice Behavior KW - Cohort Studies KW - Female KW - Food Habits KW - Food Preferences KW - Gene Frequency KW - Genotype KW - Georgia KW - Humans KW - Kazakhstan KW - Linear Models KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Questionnaires KW - Tajikistan KW - Taste KW - Uzbekistan KW - Young Adult AB -

Food preferences are the main factor driving food intake and choice. There are good reasons to suspect some genetic influence on food acceptance, not least because genetic factors are implicated in a number of factors that are likely to be related to food choice. In addition, some food dislikes show themselves early in life, before there is any evidence for aversive experiences. Although taste has been widely studied in regards of pure tastes such as bitter or sweet perception, the relationship between taste-related genes and food preferences has seldom been explored. In this work we investigated relationship of 37 taste-related genes with food preferences. The study was carried out during a scientific expedition through Caucasus and Central Asia (Silk Road) analyzing more than 400 samples from 5 different countries. A food preference questionnaire was administered to each participant and a DNA sample was obtained. Other information, such as age, sex, life style and anthropometrical measures, were also collected. We found significant associations with variants of: (1) TAS1R2 [Correction added after initial online publication on 27 Aug 2012. TAS1R3 was changed to TAS1R2.] gene and liking of Vodka (P= 1.6 × 10(-3)), white wine (P= 4.0 × 10(-4)) and lamb meat (P= 1.6 × 10(-3)); (2) PCLB2 gene and preference for Hot Tea (P= 8.0 × 10(-4)); (3) TPRV1 gene and beet liking (P= 3.8 × 10(-5)); and (4) ITPR3 gene and liking of both lamb meat (5.8 × 10(-4)) and sheep cheese (8.9×10(-4)). These findings give a new insight on a better understanding, of genetic factors influencing food preferences which is critical to the development of effective dietary interventions, especially for people that may be genetically not predisposed for liking specific nutrients.

VL - 77 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22888812?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 - Genomic profiling by whole-genome single nucleotide polymorphism arrays in Wilms tumor and association with relapse. JF - Genes Chromosomes Cancer Y1 - 2012 A1 - Perotti, Daniela A1 - Spreafico, Filippo A1 - Torri, Federica A1 - Gamba, Beatrice A1 - d'Adamo, Pio A1 - Pizzamiglio, Sara A1 - Terenziani, Monica A1 - Catania, Serena A1 - Collini, Paola A1 - Nantron, Marilina A1 - Pession, Andrea A1 - Bianchi, Maurizio A1 - Indolfi, Paolo A1 - D'Angelo, Paolo A1 - Fossati-Bellani, Franca A1 - Verderio, Paolo A1 - Macciardi, Fabio A1 - Radice, Paolo KW - Adolescent KW - Allelic Imbalance KW - Child KW - Child, Preschool KW - Chromosome Aberrations KW - DNA Copy Number Variations KW - Female KW - Genetic Markers KW - Genetic Predisposition to Disease KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Infant KW - Kaplan-Meier Estimate KW - Male KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Recurrence KW - Wilms Tumor AB -

Despite the excellent survival rate of Wilms tumor (WT) patients, only approximately one-half of children who suffer tumor recurrence reach second durable remission. This underlines the need for novel markers to optimize initial treatment. We investigated 77 tumors using Illumina 370CNV-QUAD genotyping BeadChip arrays and compared their genomic profiles to detect copy number (CN) abnormalities and allelic ratio anomalies associated with the following clinicopathological variables: relapse (yes vs. no), age at diagnosis (≤ 24 months vs. >24 months), and disease stage (low stage, I and II, vs. high stage, III and IV). We found that CN gains at chromosome region 1q21.1-q31.3 were significantly associated with relapse. Additional genetic events, including allelic imbalances at chromosome arms 1p, 1q, 3p, 3q, and 14q were also found to occur at higher frequency in relapsing tumors. Interestingly, allelic imbalances at 1p and 14q also showed a borderline association with higher tumor stages. No genetic events were found to be associated with age at diagnosis. This is the first genome wide analysis with single nucleotide polymorphism (SNP) arrays specifically investigating the role of genetic anomalies in predicting WT relapse on cases prospectively enrolled in the same clinical trial. Our study, besides confirming the role of 1q gains, identified a number of additional candidate genetic markers, warranting further molecular investigations.

VL - 51 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22407497?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 - Gastroesophageal reflux disease at any cost: a dangerous paediatric attitude. JF - Acta Paediatr Y1 - 2011 A1 - Taddio, Andrea A1 - Bersanini, Chiara A1 - Basile, Lucio A1 - Fontana, Massimo A1 - Ventura, Alessandro KW - Diagnostic Errors KW - Gastroesophageal Reflux KW - Humans KW - Inappropriate Prescribing KW - Infant KW - Infant, Newborn KW - Male KW - Proton Pump Inhibitors KW - Spasms, Infantile VL - 100 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21480985?dopt=Abstract ER - TY - JOUR T1 - Gastrointestinal Foxp3 expression in normal, inflammatory and neoplastic conditions. JF - Pathology Y1 - 2011 A1 - Villanacci, Vincenzo A1 - Not, Tarcisio A1 - Nascimbeni, Riccardo A1 - Ferrara, Fortunato A1 - Tommasini, Alberto A1 - Manenti, Stefania A1 - Antonelli, Elisabetta A1 - Bassotti, Gabrio KW - Adult KW - Aged KW - Celiac Disease KW - Cell Count KW - Disease Progression KW - Esophagitis KW - Female KW - Forkhead Transcription Factors KW - Gastric Mucosa KW - Gastritis KW - Humans KW - Inflammatory Bowel Diseases KW - Lymphocytes KW - Male KW - Middle Aged KW - Precancerous Conditions KW - Stomach Diseases KW - Stomach Neoplasms KW - Young Adult AB -

BACKGROUND: Foxp3(+) regulatory T lymphocytes (T-regs) represent an important regulatory cell subset in inflammatory, preneoplastic and neoplastic conditions of the gastrointestinal tract.

METHODS: Inflammatory, preneoplastic and neoplastic conditions of the gastrointestinal tract (189 cases) were studied with the evaluation of Foxp3 regulatory T cells based on immunohistochemistry.

RESULTS: Few Foxp3(+) cells were found in controls and inflammatory conditions (oesophagitis, gastritis, coeliac disease, inflammatory bowel disease); in preneoplastic and neoplastic conditions the number of Foxp3(+) cells was significatively increased.

CONCLUSIONS: In normal conditions the number of mucosal lymphocytes is very low throughout the gastro-intestinal tract; in active coeliac disease patients or on a gluten-free diet, only a slight increase in Foxp3(+) cells may be found. Gastrointestinal cancers are associated with higher Foxp3(+) cell proportion, compared with microscopically normal tissue and with precancerous conditions. However, it is uncertain whether the increase in these regulatory cells is a cause or a consequence of tumour progression.

VL - 43 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21670722?dopt=Abstract ER - TY - JOUR T1 - Genetic predictors of glucocorticoid response in pediatric patients with inflammatory bowel diseases. JF - J Clin Gastroenterol Y1 - 2011 A1 - De Iudicibus, Sara A1 - Stocco, Gabriele A1 - Martelossi, Stefano A1 - Londero, Margherita A1 - Ebner, Egle A1 - Pontillo, Alessandra A1 - Lionetti, Paolo A1 - Barabino, Arrigo A1 - Bartoli, Fiora A1 - Ventura, Alessandro A1 - Decorti, Giuliana KW - Adolescent KW - Child KW - Drug Resistance KW - Female KW - Follow-Up Studies KW - Genotype KW - Glucocorticoids KW - Humans KW - Inflammatory Bowel Diseases KW - Male KW - Multivariate Analysis KW - Polymorphism, Genetic KW - Receptors, Glucocorticoid KW - Regression Analysis KW - Retrospective Studies KW - Sex Factors KW - Treatment Outcome AB -

BACKGROUND: Glucocorticoids (GCs) are used in moderate-to-severe inflammatory bowel diseases (IBD) but their effect is often unpredictable.

AIM: To determine the influence of 4 polymorphisms in the GC receptor [nuclear receptor subfamily 3, group C, member 1 (NR3C1)], interleukin-1β (IL-1β), and NACHT leucine-rich-repeat protein 1 (NALP1) genes, on the clinical response to steroids in pediatric patients with IBD.

METHODS: One hundred fifty-four young IBD patients treated with GCs for at least 30 days and with a minimum follow-up of 1 year were genotyped. The polymorphisms considered are the BclI in the NR3C1 gene, C-511T in IL-1β gene, and Leu155His and rs2670660/C in NALP1 gene. Patients were grouped as responder, dependant, and resistant to GCs. The relation between GC response and the genetic polymorphisms considered was examined using univariate, multivariate, and Classification and Regression Tree (CART) analysis.

RESULTS: Univariate analysis showed that BclI polymorphism was more frequent in responders compared with dependant patients (P=0.03) and with the combined dependant and resistant groups (P=0.02). Moreover, the NALP1 Leu155His polymorphism was less frequent in the GC responsive group compared with resistant (P=0.0059) and nonresponder (P=0.02) groups. Multivariate analysis comparing responders and nonresponders confirmed an association between BclI mutated genotype and steroid response (P=0.030), and between NALP1 Leu155His mutant variant and nonresponders (P=0.033). An association between steroid response and male sex was also observed (P=0.034). In addition, Leu155His mutated genotype was associated with steroid resistance (P=0.034). Two CART analyses supported these findings by showing that BclI and Leu155His polymorphisms had the greatest effect on steroid response (permutation P value=0.046). The second CART analysis also identified age of disease onset and male sex as important variables affecting response.

CONCLUSIONS: These results confirm that genetic and demographic factors may affect the response to GCs in young patients with IBD and strengthen the importance of studying high-order interactions for predicting response.

VL - 45 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20697295?dopt=Abstract ER - TY - JOUR T1 - A genome-wide approach identifies that the aspartate metabolism pathway contributes to asparaginase sensitivity. JF - Leukemia Y1 - 2011 A1 - Chen, S-H A1 - Yang, W A1 - Fan, Y A1 - Stocco, G A1 - Crews, K R A1 - Yang, J J A1 - Paugh, S W A1 - Pui, C-H A1 - Evans, W E A1 - Relling, M V KW - Antineoplastic Agents KW - Asparaginase KW - Aspartic Acid KW - Cell Line KW - Genome-Wide Association Study KW - Humans KW - Multivariate Analysis KW - Polymorphism, Single Nucleotide KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma AB -

Asparaginase is an important component for treatment of childhood acute lymphoblastic leukemia (ALL). The basis for interindividual differences in asparaginase sensitivity remains unclear. To comprehensively identify genetic variants important in the cytotoxicity of asparaginase, we used a genome-wide association approach using the HapMap lymphoblastoid cell lines (87 CEU trio members) and 54 primary ALL leukemic blast samples at diagnosis. Asparaginase sensitivity was assessed as the drug concentration necessary to inhibit 50% of growth (inhibitory concentration (IC)(50)). In CEU lines, we tested 2,390,203 single-nucleotide polymorphism (SNP) genotypes at the individual SNP (P<0.001) and gene level (P<0.05), and identified 329 SNPs representing 94 genes that were associated with asparaginase IC(50). The aspartate metabolism pathway was the most overrepresented among 199 pathways evaluated (P=8.1 × 10(-3)), with primary involvement of adenylosuccinate lyase and aspartyl-tRNA synthetase genes. We validated that SNPs in the aspartate metabolism pathway were also associated with asparaginase sensitivity in primary ALL leukemic blast samples (P=5.5 × 10(-5)). Our genome-wide interrogation of CEU cell lines and primary ALL blasts revealed that inherited genomic interindividual variation in a plausible candidate pathway can contribute to asparaginase sensitivity.

VL - 25 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21072045?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 - Geraniol rescues inflammation in cellular and animal models of mevalonate kinase deficiency. JF - In Vivo Y1 - 2011 A1 - Marcuzzi, Annalisa A1 - Crovella, Sergio A1 - Pontillo, Alessandra KW - Animals KW - Anti-Inflammatory Agents KW - Cell Line KW - Diphosphonates KW - Disease Models, Animal KW - Inflammation KW - Lipopolysaccharides KW - Mevalonate Kinase Deficiency KW - Mice KW - Mice, Inbred BALB C KW - Monocytes KW - Nitric Oxide KW - Terpenes AB -

BACKGROUND/AIM: The inhibition of the mevalonate pathway through genetic defects such as mevalonate kinase deficiency (MKD) or pharmacological drugs such as aminobisphosphonates causes a shortage of intermediate compounds, in particular geranylgeranyl-pyrophosphate (GGPP), which is associated with the consequent augmented IL-1β release in monocytes. Considering that, due to its biochemical structure, isoprenoid geraniol enters the mevalonate pathway and may revert the genetic or pharmacological inhibition, the present study tested isoprenoid geraniol in cellular and animal MKD models obtained through the use of aminobisphosphonate pamidronate.

MATERIALS AND METHODS: The effect of natural isoprenoid geraniol on bacterial induced-inflammation was evaluated in a monocytic cell line (Raw 264.7) and in Balb/c mice treated with pamidronate.

RESULTS: Geraniol diminished the levels of inflammatory markers induced by pamidronate stimuli in vitro and in vivo.

CONCLUSION: Geraniol may be proposed as a novel therapeutic approach for the orphan disease MKD, and may also be considered for the evaluation of possible inflammatory side-effects of aminobisphosphonates.

VL - 25 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21282739?dopt=Abstract ER - TY - JOUR T1 - "GINEXMAL RCT: Induction of labour versus expectant management in gestational diabetes pregnancies". JF - BMC Pregnancy Childbirth Y1 - 2011 A1 - Maso, Gianpaolo A1 - Alberico, Salvatore A1 - Wiesenfeld, Uri A1 - Ronfani, Luca A1 - Erenbourg, Anna A1 - Hadar, Eran A1 - Yogev, Yariv A1 - Hod, Moshe KW - Adolescent KW - Adult KW - Cesarean Section KW - Diabetes, Gestational KW - Female KW - Gestational Age KW - Humans KW - Intention to Treat Analysis KW - Labor, Induced KW - Patient Selection KW - Pregnancy KW - Pregnancy Outcome KW - Research Design KW - Watchful Waiting KW - Young Adult AB -

BACKGROUND: Gestational diabetes (GDM) is one of the most common complications of pregnancies affecting around 7% of women. This clinical condition is associated with an increased risk of developing fetal macrosomia and is related to a higher incidence of caesarean section in comparison to the general population. Strong evidence indicating the best management between induction of labour at term and expectant monitoring are missing.

METHODS/DESIGN: Pregnant women with singleton pregnancy in vertex presentation previously diagnosed with gestational diabetes will be asked to participate in a multicenter open-label randomized controlled trial between 38+0 and 39+0 gestational weeks. Women will be recruited in the third trimester in the outpatient clinic or in the Day Assessment Unit according to local protocols. Women who opt to take part will be randomized according to induction of labour or expectant management for spontaneous delivery. Patients allocated to the induction group will be admitted to the obstetric ward and offered induction of labour via use of prostaglandins, Foley catheter or oxytocin (depending on clinical conditions). Women assigned to the expectant arm will be sent to their domicile where they will be followed up until delivery, through maternal and fetal wellbeing monitoring twice weekly. The primary study outcome is the Caesarean section (C-section) rate, whilst secondary measurements are maternal and neonatal outcomes. A total sample of 1760 women (880 each arm) will be recruited to identify a relative difference between the two arms equal to 20% in favour of induction, with concerns to C-section rate. Data will be collected until mothers and newborns discharge from the hospital. Analysis of the outcome measures will be carried out by intention to treat.

DISCUSSION: The present trial will provide evidence as to whether or not, in women affected by gestational diabetes, induction of labour between 38+0 and 39+0 weeks is an effective management to ameliorate maternal and neonatal outcomes. The primary objective is to determine whether caesarean section rate could be reduced among women undergoing induction of labour, in comparison to patients allocated to expectant monitoring. The secondary objective consists of the assessment and comparison of maternal and neonatal outcomes in the two study arms. .

VL - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21507262?dopt=Abstract ER - TY - JOUR T1 - Glutamine-enriched nutrition does not reduce mucosal morbidity or complications after stem-cell transplantation for childhood malignancies: a prospective randomized study. JF - Transplantation Y1 - 2011 A1 - Uderzo, Cornelio A1 - Rebora, Paola A1 - Marrocco, Emanuela A1 - Varotto, Stefania A1 - Cichello, Francesca A1 - Bonetti, Maurizio A1 - Maximova, Natalia A1 - Zanon, Davide A1 - Fagioli, Franca A1 - Nesi, Francesca A1 - Masetti, Riccardo A1 - Masetti, Roberto A1 - Rovelli, Attilio A1 - Rondelli, Roberto A1 - Valsecchi, Maria Grazia A1 - Cesaro, Simone KW - Adolescent KW - Analgesia KW - Child KW - Child, Preschool KW - Double-Blind Method KW - Female KW - Glutamine KW - Hematopoietic Stem Cell Transplantation KW - Humans KW - Infant KW - Male KW - Mucositis KW - Mucous Membrane KW - Neoplasms KW - Odds Ratio KW - Parenteral Nutrition KW - Prospective Studies KW - Recurrence KW - Stem Cells KW - Treatment Outcome AB -

BACKGROUND: Intravenous glutamine-enriched solution seems to be effective in posttransplant period in decreasing the severity and duration of mucositis. The aim of this randomized study was to determine the benefit of glutamine supplementation both on mucosal morbidity and in posttransplant associated complications.

METHODS: Children undergoing allogeneic hematopoietic stem-cell transplantation (HSCT) for malignant hematological diseases were randomly assigned to standard total parenteral nutrition (S-TPN) or glutamine-enriched (GE)-TPN solution consisting of 0.4 g/kg/day of l-alanine-glutamine dipeptide. This treatment started on the day of HSCT and ended when the patients could orally cover more than 50% of their daily energy requirements. The severity and the rate of post-HSCT mucositis were based on World Health Organization criteria. All the analyses were conducted on intention-to-treat principle.

RESULTS: One hundred twenty consecutive patients (83 men; median age, 8.1 years) were enrolled. The mean duration of treatment was 23.5 and 23 days in the two treatment arms. The mean calorie intake was 1538 kcal/d in the S-TPN group and 1512 kcal/d in GE-TPN group. All patients were well nourished before and after HSCT. Mucositis occurred in 91.4% and 91.7% of patients in S-TPN and GE-TPN arm, respectively (P=0.98). Odds ratio adjusted by type of HSCT was 0.98 (95% confidence interval, 0.26-2.63). Type and duration of analgesic treatment, clinical outcome (engraftment, graft versus host disease, early morbidity, and mortality, relapse rate up to 180 days post-HSCT) were not significantly different in the two treatment arms.

CONCLUSION: GE-TPN solution does not affect mucositis and outcome in well-nourished HSCT allogeneic patients.

VL - 91 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21499196?dopt=Abstract ER - TY - JOUR T1 - A G to C transversion at the last nucleotide of exon 25 of the MYH9 gene results in a missense mutation rather than in a splicing defect. JF - Eur J Med Genet Y1 - 2010 A1 - Vettore, Silvia A1 - De Rocco, Daniela A1 - Gerber, Bernhard A1 - Scandellari, Raffaella A1 - Bianco, Anna Monica A1 - Balduini, Carlo L A1 - Pecci, Alessandro A1 - Fabris, Fabrizio A1 - Savoia, Anna KW - Adolescent KW - Adult KW - Blood Platelets KW - Computational Biology KW - Exons KW - Female KW - Humans KW - Inclusion Bodies KW - Kidney Failure, Chronic KW - Molecular Motor Proteins KW - Mutation, Missense KW - Myosin Heavy Chains KW - Neutrophils KW - Nonmuscle Myosin Type IIA KW - Nucleotides KW - RNA Splicing KW - Thrombocytopenia AB -

MYH9-related disease (MYH9-RD) is a rare autosomal dominant disorder caused by mutations in MYH9, the gene encoding the heavy chain of non-muscle myosin IIA. Patients present with congenital macrothrombocytopenia and inclusion bodies in neutrophils and might develop sensorineural deafness, presenile cataract, and/or progressive nephropathy leading to end-stage renal failure. In two families with macrothrombocytopenia we identified a novel c.3485G > C mutation in the last nucleotide of exon 25. Bioinformatic tools for splice site prediction and minigene functional test predicted splicing anomalies of exon 25. However, analysis of RNA purified from patient's peripheral blood did not allowed us to detect any anomalies, suggesting that RNA processing is correct at least in this tissue. Therefore, we concluded that c.3485G > C leads to a novel missense mutation (p.Arg1162Thr) of myosin-9, which resulted to be slightly degraded in patient platelets. A precise definition of the effect of mutations is fundamental to improve our knowledge into the pathogenetic mechanisms responsible for the disease.

VL - 53 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20603234?dopt=Abstract ER - TY - JOUR T1 - Genetic polymorphism of inosine-triphosphate-pyrophosphatase influences mercaptopurine metabolism and toxicity during treatment of acute lymphoblastic leukemia individualized for thiopurine-S-methyl-transferase status. JF - Expert Opin Drug Saf Y1 - 2010 A1 - Stocco, Gabriele A1 - Crews, Kristine R A1 - Evans, William E KW - 6-Mercaptopurine KW - Antineoplastic Combined Chemotherapy Protocols KW - Child KW - Humans KW - Individualized Medicine KW - Methyltransferases KW - Models, Biological KW - Neutropenia KW - Nucleotide Transport Proteins KW - Polymorphism, Genetic KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma KW - Pyrophosphatases AB -

IMPORTANCE OF THE FIELD: Although genetic polymorphisms in the gene encoding human thiopurine methyltransferase (TPMT) are known to have a marked effect on mercaptopurine metabolism and toxicity, there are many patients with wild-type TPMT who develop toxicity. Furthermore, when mercaptopurine dosages are adjusted in patients who are heterozygous at the TPMT locus, there are still some patients who develop toxicity for reasons that are not fully understood. Therefore, we recently studied the effects of a common polymorphism in another gene encoding an enzyme involved in mercaptopurine metabolism (SNP rs1127354 in inosine-triphospate-pyrophosphatase, ITPA), showing that genetic polymorphism of ITPA is a significant determinant of mercaptopurine metabolism and of febrile neutropenia following combination chemotherapy of acute lymphoblastic leukemia (ALL) in which mercaptopurine doses are individualized based on TPMT genotype.

AREA COVERED IN THIS REVIEW: In this review, we summarize the knowledge available about the effect and clinical relevance of TPMT and ITPA on mercaptopurine pharmacogenomics, with a particular focus on the use of this medication in pediatric patients with ALL.

WHAT THE READER WILL GAIN: Reader will gain insights into: i) the effects of pharmacogenomic traits on mercaptopurine toxicity and efficacy for the treatment of ALL and ii) individualization strategies that can be used to mitigate toxicity without compromising efficacy in pediatric patients with ALL.

TAKE HOME MESSAGE: Mercaptopurine dose can be adjusted on the basis of TPMT genotype to mitigate toxicity in pediatric patients with ALL. As treatment is individualized in this way for the most relevant genetic determinant of drug response (i.e., for mercaptopurine, TPMT), the importance of other genetic polymorphisms emerges (e.g., ITPA).

VL - 9 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20021291?dopt=Abstract ER - TY - JOUR T1 - Gestational diabetes and fetal growth acceleration: induction of labour versus expectant management. JF - Minerva Ginecol Y1 - 2010 A1 - Alberico, S A1 - Businelli, C A1 - Wiesenfeld, U A1 - Erenbourg, A A1 - Maso, G A1 - Piccoli, M A1 - Ronfani, L KW - Adult KW - Body Mass Index KW - Cesarean Section KW - Diabetes, Gestational KW - Elective Surgical Procedures KW - Female KW - Fetal Development KW - Fetal Macrosomia KW - Gestational Age KW - Humans KW - Incidence KW - Infant, Newborn KW - Italy KW - Labor, Induced KW - Medical Records KW - Obesity KW - Pregnancy KW - Pregnancy Outcome KW - Retrospective Studies KW - Risk Factors KW - Statistics, Nonparametric KW - Watchful Waiting AB -

AIM: The aim of the study was to compare elective induction of labour at 38 weeks versus expectant management in A1 and A2 gestational diabetes (GDM) pregnancies with fetal growth acceleration. Primary outcome of the study was C-section (CS) rate, while secondary outcomes were macrosomia incidence and adverse perinatal outcomes.

METHODS: A retrospective cohort study was carried out. Data were collected between 1996 and 2006 and evaluated through patients' records analysis. Differences between the two study groups were investigated using non-parametric tests for continuous variables and χ2 test for categorical ones.

RESULTS: There was no significant difference between induction and expectant management in terms of caesarean section rate. A trend favoring women in the induction group in terms of incidence of macrosomia and neonatal outcomes was identified, but results were not statistically significant.

CONCLUSION: Labour induction at 38 weeks in GDM patients with fetal growth acceleration does not seem to determine an increased incidence of C-section in comparison to expectant management, particularly in case of maternal obesity.

VL - 62 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21079575?dopt=Abstract ER -