Variantes do gene CD226 associadas com a susceptibilidade ao diabetes mellitus tipo 1 autoimune / CD226 gene variants associated with susceptibility to type 1, immune mediated, diabetes

AUTOR(ES)
FONTE

IBICT - Instituto Brasileiro de Informação em Ciência e Tecnologia

DATA DE PUBLICAÇÃO

09/08/2012

RESUMO

Recently, Genome Wide Association (GWA) studies identified a new locus, 18q22, as a canditate to Type 1 A, or immune mediated diabetes (T1AD) susceptibility. This locus harbors the CD226 gene, responsible for encoding the leukocyte adhesion molecule (CD226) involved in cell adhesion, differentiation of naïve CD4+T cells, cytotoxicity induced by natural killer (NK) cells and cytokine production. Although just one single nucleotide polymorphism (SNP) rs763361 A/G had been related to T1AD, little is known about the involvement of new variants of CD226, implicated in other autoimmune disorders, in the pathogenesis of T1AD. In order to identify polymorphic variants related to T1AD susceptibility and their influences in phenotypic characteristics and other manifestations of autoimmunity, 532 type 1A diabetic patients and 594 health controls were enrolled in this study. Initially, in a subset of 106 diabetics and 102 controls, coding and flanking regions of CD226 gene obtained from genomic DNA extraction were amplified by polymerase chain reaction technique and subjected to direct sequencing. In a second step, the polymorphisms rs763361, rs727088 and rs1788101 were genotyped by TaqMan assay in the remaining patients and controls. Results: 12 variants in CD226 gene, seven of them with frequency above 5 % where identified. We did not found new variants. The variant rs727088 was not in Hardy Weinberg equilibrium in the control group. The genotypes AA (OR=1.45; p=0.005) and CC (OR=1.41; p=0.01) related to rs763361 and rs727088 variants respectively, were associated with risk of T1AD. Both predominated in female (p<0.01). Further, these variants were in linkage disequilibrium. The genotype haplotype ACAC formed by the risk variants was more frequent in patients with diabetes (30.5% x 25.6%; OR=1.42; p=0.014). The AA genotype of rs763361, the CC genotype and ACAC genotype haplotype were associated with lower levels of C-peptide in patients with no more than two years of disease course. The presence of pancreatic and extra-pancreatic autoantibodies was not associated with CD226 SNPs. Conclusion: The AA genotype of rs763361 variant of the gene CD226 predisposes to autoimmune diabetes in our population, as well as to lower levels of C-peptide, contributing to the aggressiveness of the disease. It predominated in female. Data of rs727088 variant should be analyzed with caution due to the lack of Hardy Weinberg equilibrium in the control group

ASSUNTO(S)

autoantibodies autoanticorpos cd226 gene diabetes mellitus tipo1 gene cd226 genotyping technics immune system sistema imunológico técnicas de genotipagem type 1 diabetes

ACESSO AO ARTIGO

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