MC1R gene polymorphisms analysis associated with human pigmentation phenotypes on the brazilian population

Dentre os genes conhecidos por infl uenciarem a variação normal de pigmentação de olhos, pele e cabelos em humanos, o gene MC1R (receptor de melanocortina 1) é o mais bem caracterizado até o momento. A atuação do MC1R ocorre pela produção de uma proteína transmembrana nos melanócitos, responsável pela regulação da produção de melanina nos mesmos. Sabe-se que a atuação do MC1R determina a proporção entre eumelanina (coloração castanha/preta) e feomelanina (amarela/vermelha) presente nos melanócitos. O presente trabalho tem como objetivo analisar os SNPs conhecidos do gene MC1R com o propósito de se avaliar a infl uência da diversidade deste gene em características como a presença de sardas e variação da pigmentação dos olhos, pele e cabelos em humanos. Foram analisados 29 SNPs conhecidos da região codifi cadora do gene MC1R em 296 indivíduos da região de Ribeirão Preto, SP. A extração do DNA foi feita pela técnica de salting-out. A região codifi cadora do gene MC1R (951pb) foi amplifi cada em uma única reação de PCR, a qual foi sequenciada em um analisador genético ABI-PRISM 310 por eletroforese capilar, utilizando-se os mesmos primers empregados para a amplifi cação. Dos 29 SNPs avaliados, 22 deles mostraram variação nas amostras estudadas, sendo que metade deles demonstrou estar associados a características de pigmentação. Observou-se um conjunto de SNPs associados claramente à fenótipos relacionados à feomelanina (+1645 A, +1831 T,+1858 T e +2260 C), enquanto outros se relacionam à ocorrência de eumelanina (+1558 G, +2322 G, +2346 A). O presente trabalho apresenta associações signifi cativas entre SNPs individuais e pigmentação de olhos, cabelos e pele, sendo que nosso dados confi rmam que tal gene também desempenha papel relevante na variação de pigmentação na população Brasileira.Among the known genes infl uencing eye, skin and hair normal pigmentation variation, the MC1R (melanocortin 1-receptor) gene is the best characterized so far. The activity of MC1R occurs due the production of a transmembrane protein in melanocytes, responsible for regulating the production of melanin. It is known that the performance of MC1R determines the ratio of eumelanin (brown /black color) and pheomelanin (yellow/ red) present in melanocytes. This study aims to analyze known SNPs of the MC1R gene in order to evaluate the infl uence of this gene diversity on features like freckles and pigmentation variation of eyes, skin and hair in humans. We analyzed 29 known SNPs in the coding region of MC1R gene in 296 individuals from the region of Ribeirão Preto, Brazil. DNA extraction was performed using the salting-out technique. The MC1R gene coding region (951pb) was amplifi ed in a single PCR reaction, which was sequenced on a ABI PRISM-310 genetic analyzer by capillary electrophoresis, using the same primers used for amplifi cation. Of the 29 SNPs evaluated, only 22 showed variation in the samples studied, half of them showing to be associated with pigmentation characteristics. We observed a set of SNPs clearly associated to pheomelanin (+1645 A, +1831 T,+1858 T e +2260 C), while others related to eumelanin occurrence (+1558 G, +2322 G, +2346 A). Our study shows signifi cant associations between individual SNPs and eyes, hair and skin pigmentation. The results presented here confi rm that this gene also plays a relevant role in the pigmentation variation in the Brazilian population

HFE gene polymorphism defined by sequence based typing of the Brazilian population and a standardized nomenclature for HFE allele sequences

The HFE molecule controls iron uptake from gut, and defects in the molecule have been associated with iron overload, particularly in hereditary hemochromatosis. The HFE gene including both coding and boundary intronic regions were sequenced in 304 Brazilian individuals, encompassing healthy individuals and patients exhibiting hereditary or acquired iron overload. Six sites of variation were detected: i) H63D C > G in exon 2, ii) IVS2 (+4) T > C in intron 2, iii) a C > G transversion in intron 3, iv) C282Y G > A in exon 4, v) IVS4 (-44) T > C in intron 4, and vi) a new Guanine deletion (G > del) in intron 5, which were used for haplotype inference. Nine HFE alleles were detected and six of these were officially named on the basis of the HLA Nomenclature, defined by the WHO Nomenclature Committee for Factors of the HLA System, and published via the IPD-IMGT/HLA website. Four alleles, HFE*001, 002, 003 and 004 exhibited variation within their exon sequences

HPV type infection in different anogenital sites among HIV-positive Brazilian women

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MiRNA-Mediated Control of HLA-G Expression and Function

HLA-G is a non-classical HLA class-Ib molecule expressed mainly by the extravillous cytotrophoblasts (EVT) of the placenta. The expression of HLA-G on these fetal cells protects the EVT cells from immune rejection and is therefore important for a healthy pregnancy. The mechanisms controlling HLA-G expression are largely unknown. Here we demonstrate that miR-148a and miR-152 down-regulate HLA-G expression by binding its 3′UTR and that this down-regulation of HLA-G affects LILRB1 recognition and consequently, abolishes the LILRB1-mediated inhibition of NK cell killing. We further demonstrate that the C/G polymorphism at position +3142 of HLA-G 3′UTR has no effect on the miRNA targeting of HLA-G. We show that in the placenta both miR-148a and miR-152 miRNAs are expressed at relatively low levels, compared to other healthy tissues, and that the mRNA levels of HLA-G are particularly high and we therefore suggest that this might enable the tissue specific expression of HLA-G

Implications of the polymorphism of HLA-G on its function, regulation, evolution and disease association

The HLA-G gene displays several peculiarities that are distinct from those of classical HLA class I genes. The unique structure of the HLA-G molecule permits a restricted peptide presentation and allows the modulation of the cells of the immune system. Although polymorphic sites may potentially influence all biological functions of HLA-G, those present at the promoter and 3′ untranslated regions have been particularly studied in experimental and pathological conditions. The relatively low polymorphism observed in the MHC-G coding region both in humans and apes may represent a strong selective pressure for invariance, whereas, in regulatory regions several lines of evidence support the role of balancing selection. Since HLA-G has immunomodulatory properties, the understanding of gene regulation and the role of polymorphic sites on gene function may permit an individualized approach for the future use of HLA-G for therapeutic purposes

Relationship between HLA antigens and infectious agents in contributing towards the development of Graves' disease

Graves' disease (GD) is an autoimmune thyroid disorder which is associated with the human leucocyte antigens HLA-DR3 and DQA1* O501 in Caucasians. We have explored the possibility that some patients with certain HLA specificities develop anti-HLA antibodies which are correlated with environmental factors that may contribute to the development of GD. We studied 40 GD patients and 157 healthy individuals (controls). Serology was used to type HLA-A -B, -Cw, and -DR antigens. The frequencies of these antigens in relation to lymphocytotoxic anti-HLA-A-B-Cw-DR antibodies and two environmental factors (Yersinia enterocolitica and Coxsackie B virus) were determined. The frequencies of HLA-B15, -B21 and DR3 antigens were increased, whereas HLA-DRS antigen was decreased in GD patients. A significant association between HLA-DR3 antigen and lymphocytotoxic antibodies was observed, i. e., IgGs from GD patients were cytotoxic to HLA-DR3+ normal B cells. Following absorption with Yersinia enterocolitica or Coxsackie-B-virus, only Coxsackie-B virus completely inhibited the lymphocytotoxic reactions against HLA-DR3(+) B cells. Besides confirming the association of HLA-DR3 with GD, this study also suggests the role of Coxsackie-reative HLA-DR3 antibodies as contributing factors to the pathogenesis of the disease.2741671172

LIG4 and RAD52 DNA repair genes polymorphisms and systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder with a strong genetic background. Nevertheless, SLE might also be triggered due to environmental factors, such as UV light exposure. DNA double strand breaks (DSBs) may be induced secondarily by UV radiation, increasing DNA immunogenicity and in SLE patients DNA repair is diminished, allowing the accumulation of DSBs and genomic instability. LIG4 and RAD52 genes play important roles in DNA repair mechanisms and a recent microarray analysis showed their differential expression in active SLE patients. In this study we investigated a potential association between LIG4 and RAD52 single nucleotide polymorphisms (SNPs) and SLE predisposition in a Southeast Brazilian population. We assessed four Tag SNPs in LIG4 and three in RAD52 gene region, encompassing most of the gene sequence, in 158 SLE patients and 212 healthy controls. We also performed SNPs analysis considering clinical manifestation, gender and ethnicity in SLE patients. Our data did not show association between LIG4 and RAD52 SNPs and SLE, its clinical manifestations or ethnicity in the tested population. The analysis regarding ethnicity and SLE clinical manifestations indicated Caucasian-derived patients as more susceptible to cutaneous and hematological alterations than the African-derived. To our knowledge, this is the first association study involving LIG4 and RAD52 genes and SLE predisposition

Molecular mechanisms associated with donor-specific microchimerism in peripheral blood of Brazilian patients after liver transplantation

A large number of studies in liver transplantation have demonstrated allogeneic microchimerism. The clinical and immunologic implications of this finding remain inconclusive, just as the influence of HLA mismatch and donor alloreactivity also are controversial. The present study analyzed the presence of allogeneic microchimerism in liver transplant recipients in relation to donor leukocyte kinetics and rejection episodes. The study was extended to determining the influence of immunogenetic factors in patients after liver transplantation. The presence of allogeneic microchimerism was analyzed on peripheral blood of 50 recipients. DNA extracted from the samples was subjected to typing for HLA-DRB1 and -DQB1 alleles by polymerase chain reactions using sequence-specific primers (PCR/SSP). Microchimerism was identified by nested PCR/SSP. Microchimerism was detected in 72% of patients. There was significant effect of microchimerism on rejection episodes (P =.002), while HLA mismatches did not show significance for one or two mismatches (P =.98). Allogeneic microchimerism detected in the majority of liver transplant patients was observed to be significantly associated with rejection episodes.3851411141