@article {8287, title = {MBL2 genetic polymorphisms and HIV-1 mother-to-child transmission in Zambia.}, journal = {Immunol Res}, volume = {64}, year = {2016}, month = {2016 Jun}, pages = {775-84}, abstract = {

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

}, issn = {1559-0755}, doi = {10.1007/s12026-015-8779-1}, author = {Zupin, Luisa and Polesello, Vania and Segat, Ludovica and Kuhn, Louise and Crovella, Sergio} } @article {7758, title = {MBL2 polymorphisms in women with atypical squamous cells of undetermined significance.}, journal = {J Med Virol}, volume = {87}, year = {2015}, month = {2015 May}, pages = {851-9}, abstract = {

Infection with high risk Human papillomavirus (HPV) is the main known cause of cervical cancer. HPV induces different grades of lesions: among them, Atypical squamous cells of undetermined significance are abnormal lesions that could evolve in pre-cancer lesions or spontaneously regress. The mannose binding lectin (MBL) is an innate immunity serum protein also found in cervico-vaginal mucosa, whose expression is known to be affected by polymorphisms in exon 1 and promoter of the MBL2 gene. In the present study the possible association between MBL2 functional polymorphisms and susceptibility to develop atypical squamous cells of undetermined significance was investigated in a group of women from North-East of Italy, stratified for HPV infection status. The MBL2 D and O alleles and the deficient producer combined genotypes, responsible for low MBL production, were more represented among atypical squamous cells of undetermined significance positive women than healthy controls and the results were confirmed when only HPV negative samples were considered. These results suggest a possible involvement of MBL2 functional polymorphisms in atypical squamous cells of undetermined significance susceptibility.

}, keywords = {Adolescent, Adult, Atypical Squamous Cells of the Cervix, Female, Gene Frequency, Genetic Predisposition to Disease, Humans, Italy, Mannose-Binding Lectin, Polymorphism, Single Nucleotide, Young Adult}, issn = {1096-9071}, doi = {10.1002/jmv.24080}, author = {Zupin, Luisa and Polesello, Vania and Casalicchio, Giorgia and Freato, Nadia and Maestri, Iva and Comar, Manola and Crovella, Sergio and Segat, Ludovica} } @article {7750, title = {Meta-analysis and time series modeling allow a systematic review of primary HIV-1 drug-resistant prevalence in Latin America and Caribbean.}, journal = {Curr HIV Res}, volume = {13}, year = {2015}, month = {2015}, pages = {125-42}, abstract = {

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

}, issn = {1873-4251}, author = {Coelho, Ant{\^o}nio Victor Campos and De Moura, Ronald Rodrigues and da Silva, Ronaldo Celerino and Kamada, Anselmo Jiro and Guimar{\~a}es, Rafael Lima and Brand{\~a}o, Lucas Andr{\'e} Cavalcanti and Coelho, Hem{\'\i}lio Fernandes Campos and Crovella, Sergio} } @article {7770, title = {Meta-analysis of Brazilian genetic admixture and comparison with other Latin America countries.}, journal = {Am J Hum Biol}, volume = {27}, year = {2015}, month = {2015 Sep-Oct}, pages = {674-80}, abstract = {

OBJECTIVES: This study aims at performing a systematic review and meta-analysis with the studies of genetic admixture inference of Brazilian population and to compare these results with the genetic admixture levels in other Latin American countries.

METHODS: We searched for articles regarding the estimation of Brazilian genetic admixture published between 1980 and 2014 that used autosomal markers. Then, conducted meta-analyses at the whole-country and regional level. Finally, we compared the results of Brazil with other estimates from other South, Central and North American countries.

RESULTS: We analyzed data from 25 studies in 38 different Brazilian populations. European (EUR) ancestry is the major contributor to the genetic background of Brazilians, followed by African (AFR), and Amerindian (AMR) ancestries. The pooled ancestry contributions were 0.62 EUR, 0.21 AFR, and 0.17AMR. The Southern region had a greater EUR contribution (0.77) than other regions. Individuals from the Northeast (NE) region had the highest AFR contribution (0.27) whereas individuals from the North regions had more AMR contribution (0.32). In the Latin America context, Brazil has the 5th high EUR contribution, the 12th for the AFR component and the 10th for the AMR ancestry.

CONCLUSIONS: Admixture proportions vary greatly among Brazilian populations and also through Latin America. More studies in the Center-West, North and NE regions are needed to capture a more complete picture of the genomic ancestry of Brazil.

}, issn = {1520-6300}, doi = {10.1002/ajhb.22714}, author = {Moura, Ronald Rodrigues de and Coelho, Ant{\^o}nio Victor Campos and Balbino, Valdir de Queiroz and Crovella, Sergio and Brand{\~a}o, Lucas Andr{\'e} Cavalcanti} } @article {7714, title = {Mevalonate Pathway Blockade, Mitochondrial Dysfunction and Autophagy: A Possible Link.}, journal = {Int J Mol Sci}, volume = {16}, year = {2015}, month = {2015}, pages = {16067-84}, abstract = {

The mevalonate pathway, crucial for cholesterol synthesis, plays a key role in multiple cellular processes. Deregulation of this pathway is also correlated with diminished protein prenylation, an important post-translational modification necessary to localize certain proteins, such as small GTPases, to membranes. Mevalonate pathway blockade has been linked to mitochondrial dysfunction: especially involving lower mitochondrial membrane potential and increased release of pro-apoptotic factors in cytosol. Furthermore a severe reduction of protein prenylation has also been associated with defective autophagy, possibly causing inflammasome activation and subsequent cell death. So, it is tempting to hypothesize a mechanism in which defective autophagy fails to remove damaged mitochondria, resulting in increased cell death. This mechanism could play a significant role in Mevalonate Kinase Deficiency, an autoinflammatory disease characterized by a defect in Mevalonate Kinase, a key enzyme of the mevalonate pathway. Patients carrying mutations in the MVK gene, encoding this enzyme, show increased inflammation and lower protein prenylation levels. This review aims at analysing the correlation between mevalonate pathway defects, mitochondrial dysfunction and defective autophagy, as well as inflammation, using Mevalonate Kinase Deficiency as a model to clarify the current pathogenetic hypothesis as the basis of the disease.

}, issn = {1422-0067}, doi = {10.3390/ijms160716067}, author = {Tricarico, Paola Maura and Crovella, Sergio and Celsi, Fulvio} } @article {7688, title = {Microglia activation and interaction with neuronal cells in a biochemical model of mevalonate kinase deficiency.}, journal = {Apoptosis}, volume = {20}, year = {2015}, month = {2015 Aug}, pages = {1048-55}, abstract = {

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

}, issn = {1573-675X}, doi = {10.1007/s10495-015-1139-8}, author = {Tricarico, Paola Maura and Piscianz, Elisa and Monasta, Lorenzo and Kleiner, Giulio and Crovella, Sergio and Marcuzzi, Annalisa} } @article {3505, title = {Mevalonate kinase deficiency and IBD: shared genetic background.}, journal = {Gut}, volume = {63}, year = {2014}, month = {2014 Aug}, pages = {1367-8}, keywords = {Genetic Predisposition to Disease, Humans, Inflammatory Bowel Diseases}, issn = {1468-3288}, doi = {10.1136/gutjnl-2013-306555}, author = {Bianco, Anna Monica and Girardelli, Martina and Vozzi, Diego and Crovella, Sergio and Kleiner, Giulio and Marcuzzi, Annalisa} } @article {1928, title = {Mevalonate kinase deficiency: disclosing the role of mevalonate pathway modulation in inflammation.}, journal = {Curr Pharm Des}, volume = {18}, year = {2012}, month = {2012}, pages = {5746-52}, abstract = {

Inflammation is a highly regulated process involved both in the response to pathogens as well as in tissue homeostasis. In recent years, a complex network of proteins in charge of inflammation control has been revealed by the study of hereditary periodic fever syndromes. Most of these proteins belong to a few families and share the capability of sensing pathogen-associated and damageassociated molecular patterns. By interacting with each other, these proteins participate in the assembly of molecular platforms, called inflammasomes, which ultimately lead to the activation of cytokines, to the transcription of inflammatory genes or to the induction of cell apoptosis. Among hereditary periodic fever syndromes, mevalonate kinase deficiency (MKD) is the sole in which the phenotype did not directly associate with a deficiency of these proteins, but with a metabolic defect of the mevalonate pathway, highlighting the importance of this metabolic pathway in the inflammation control. Noteworthy, drugs acting on this pathway can greatly influence the inflammatory response. The modulation of inflammation by mevalonate pathway is of interest, since it may involve mechanisms not directly referable to inflammasomes. MKD provides a model to study these mechanisms and possibly to develop new classes of anti-inflammatory drugs.

}, keywords = {Animals, Anti-Inflammatory Agents, Apoptosis, Cytokines, Drug Design, Hereditary Autoinflammatory Diseases, Humans, Inflammasomes, Inflammation, Mevalonate Kinase Deficiency, Mevalonic Acid}, issn = {1873-4286}, author = {Marcuzzi, Annalisa and Crovella, Sergio and Monasta, Lorenzo and Vecchi Brumatti, Liza and Gattorno, Marco and Frenkel, Joost} } @article {1746, title = {Mannose binding lectin gene (MBL2) functional polymorphisms are associated with systemic lupus erythematosus in southern Brazilians.}, journal = {Hum Immunol}, volume = {72}, year = {2011}, month = {2011 Jun}, pages = {516-21}, abstract = {

Susceptibility to systemic lupus erythematosus (SLE) has been associated with immunologic, environmental, and genetic factors. To uncover a possible association between MBL2 gene polymorphisms and SLE, we analyzed functional polymorphisms in the promoter and first exon of the MBL2 gene in 134 Brazilian SLE patients and 101 healthy controls. Genotype and allele frequencies of MBL2 A/O polymorphism were significantly different between patients and controls, and the O allele was associated with an increased risk of SLE. An association between low mannose binding lectin (MBL) producer combined genotypes and increased risk for SLE was also reported. Furthermore, when stratifying SLE patients according to clinical and laboratory data, an association between the A/O genotype and nephritic disorders and between the X/Y genotype and antiphospholipid syndrome was evident. Combined genotypes responsible for low MBL production were more frequently observed in SLE patients with nephritis. Our results indicate MBL2 polymorphisms as possible risk factors for SLE development and disease-related clinical manifestations.

}, keywords = {Adolescent, Adult, Aged, Brazil, DNA Mutational Analysis, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Lupus Erythematosus, Systemic, Male, Mannose-Binding Lectin, Middle Aged, Polymorphism, Genetic, Population Groups, Promoter Regions, Genetic}, issn = {1879-1166}, doi = {10.1016/j.humimm.2011.03.007}, author = {Sandrin-Garcia, Paula and Brand{\~a}o, Lucas Andr{\'e} Cavalcanti and Coelho, Ant{\^o}nio Victor Campos and Guimar{\~a}es, Rafael Lima and Pancoto, Jo{\~a}o Alexandre Tr{\'e}s and Segat, Ludovica and Donadi, Eduardo Ant{\^o}nio and de Lima-Filho, Jos{\'e} Luiz and Crovella, Sergio} } @article {1619, title = {Mannose-binding lectin gene (MBL-2) polymorphism in oral lichen planus.}, journal = {Clin Oral Investig}, volume = {15}, year = {2011}, month = {2011 Oct}, pages = {699-704}, abstract = {

TNF-α may be associated with the etiopathogenesis of oral lichen planus (OLP), and it has been suggested that polymorphism of mannose-binding lectin (MBL) increases the in vitro production of TNF- α. The aim of the present study was to assess the relevance of genetic diversity of MBL in OLP. The study sample comprised 90 individuals, 45 OLP patients and 45 healthy volunteers. MBL-2 gene was amplified using real-time PCR. Frequency of A/A genotype was 55.6\% in OLP and 53.3\% in healthy volunteers. Likewise, A/0 heterozygote genotype was found in 42.2\% and 35.6\%; 2.2\% and 11.1\%, had the recessive 0/0 genotype respectively. Frequencies of the "A" and "0" alleles were 77\% and 23\% in the OLP group and 71.2\% in control group. There were no statistically significant differences regarding genotype frequency (p = 0.546) or allele frequency (p = 0.497). In conclusion, no significant association was found between polymorphism of MBL-2 gene and OLP.

}, keywords = {Adolescent, Adult, Aged, Female, Gene Expression Regulation, Gene Frequency, Genes, Recessive, Genetic Variation, Genotype, Heterozygote, Homozygote, Humans, Lichen Planus, Oral, Male, Mannose-Binding Lectin, Middle Aged, Mutation, Polymorphism, Genetic, Real-Time Polymerase Chain Reaction, Tumor Necrosis Factor-alpha, Young Adult}, issn = {1436-3771}, doi = {10.1007/s00784-010-0428-4}, author = {Barkokebas, Andreza and de Albuquerque T Carvalho, Alessandra and de Souza, Paulo Roberto Eleut{\'e}rio and Gomez, Ricardo Santiago and Xavier, Guilherme Machado and Ribeiro, Camila Maria Beder and Crovella, Sergio and Porter, Stephen Ross and Le{\~a}o, Jair Carneiro} } @article {1811, title = {MBL1 gene in nonhuman primates.}, journal = {Hum Immunol}, volume = {72}, year = {2011}, month = {2011 Nov}, pages = {1084-90}, abstract = {

With the aim of investigating the evolution of MBL1P1 (MBL1) gene, we analyzed the MBL1 coding region sequences in several specimens of two species of great apes, two species of Hylobatidae, four species of Cercopithecidae, and one Platyrrhine species, and in human beings. An indication for a progressive silencing of the molecule has been found. We found a \~{}300 bp insertion in the first intron of MBL1 in the Cercopithecidae that could explain the different splicing between primates species and possibly why Macaca mulatta is able to produce a complete protein, whereas in human beings the protein product is truncated. Based on our genetic findings, we could speculate that all the Cercopithecidae (presenting the 300-bp insertion) may express MBL1 mature protein like the M mulatta, whereas the lesser and great apes, which lack this insertion as do human beings, may have only the truncated pseudogene.

}, keywords = {Animals, Base Sequence, Evolution, Molecular, Gene Silencing, Genome, Humans, Mannose-Binding Lectin, Molecular Sequence Data, Multigene Family, Phylogeny, Polymorphism, Genetic, Primates, Pseudogenes, Sequence Alignment, Sequence Analysis, DNA, Sequence Deletion, Species Specificity}, issn = {1879-1166}, doi = {10.1016/j.humimm.2011.08.009}, author = {Segat, Ludovica and Crovella, Sergio} } @article {1690, title = {The missense variation Q705K in CIAS1/NALP3/NLRP3 gene and an NLRP1 haplotype are associated with celiac disease.}, journal = {Am J Gastroenterol}, volume = {106}, year = {2011}, month = {2011 Mar}, pages = {539-44}, abstract = {

OBJECTIVES: Celiac disease (CD) is a multifactorial common disorder with several susceptibility loci. Variations in the NALP1/NLRP1 and NALP3/NLRP3 genes have been reported to confer risk for several autoimmune conditions. We hypothesized that polymorphisms in these genes, due to their role in innate immunity and inflammatory processes, may affect susceptibility to CD.

METHODS: Two single-nucleotide polymorphisms (SNPs) in NLRP1 (rs12150220, rs2670660) and two SNPs (rs10754558, rs35829419) in NLRP3 genes were genotyped in 504 CD Italian patients and 256 healthy controls.

RESULTS: The minor A allele of NLRP3 rs35829419 (Q705K) polymorphism appeared to exert a protective role against the development of CD (P=0.029; odds ratio (OR)=0.56). Moreover, a particular NLRP1 haplotype was associated with predisposition to CD (P=0.003; OR=1.38), even more when present in combination with the rs35829419 major C allele (P=0.002; OR=1.42).

CONCLUSIONS: We hypothesized that the deregulation of CIAS1/NALP3/NLRP3 and NALP1/NLRP1 inflammasomes could have a role in CD pathogenesis.

}, keywords = {Adaptor Proteins, Signal Transducing, Adolescent, Apoptosis Regulatory Proteins, Carrier Proteins, Celiac Disease, Child, Child, Preschool, Female, Genetic Predisposition to Disease, Genotype, Glutamine, Haplotypes, Humans, Inflammasomes, Italy, Lysine, Male, Mutation, Missense, Polymorphism, Single Nucleotide}, issn = {1572-0241}, doi = {10.1038/ajg.2010.474}, author = {Pontillo, Alessandra and Vendramin, Anna and Catamo, Eulalia and Fabris, Annalisa and Crovella, Sergio} }