RESUMO
Type 1 diabetes (T1D) is a T-cell-mediated autoimmune disease. Although the precise mechanisms leading to the destruction of islet beta cells are unknown, diverse studies support a role of the CXCR3-binding chemokines. A combination of a case (n = 447)-control (n = 300) and family (n = 221) analysis was performed to investigate the role of the CXCL9 (rs10336, rs3733236) and CXCL10 (rs3921, rs35795399 and rs8878) polymorphisms and their interaction with HLA high-risk haplotypes DQ2(DQA*0501-DQB*0201)-DQ8(DQA*0301-DQB*0302) in T1D. In addition, the mRNA expression of these genes and of the CXCR3 in peripheral blood mononuclear cells (PBMCs) of T1D patients was studied. In the family analysis, an overtransmission of the allele T and G of the polymorphisms rs35795399 and rs8878 in the whole group (p = 0.0520 and p = 0.0290, respectively) as well as in combination with the HLA-high risk haplotypes (p = 0.0209 and 0.0340, respectively) were observed. In addition, the haplotype rs8878G-rs35795399T was more often transmitted from parents to affected offspring, whereas the haplotype rs8878A-rs35795399C was less often transmitted (p = 0.0130 and p = 0.0201, respectively). Nevertheless these associations did not remain significant after correction for multiple testing, and they could not be corroborated in the case-control analysis. Although we did not find an association of the CXCL9 and CXCL10 polymorphisms with type 1 diabetes in the German population, we cannot discard their role in other populations or other autoimmune diseases.
Assuntos
Quimiocina CXCL10/genética , Quimiocina CXCL9/genética , Diabetes Mellitus Tipo 1/genética , Polimorfismo de Nucleotídeo Único , Adulto , Estudos de Casos e Controles , Quimiocina CXCL10/metabolismo , Quimiocina CXCL9/metabolismo , Saúde da Família , Feminino , Expressão Gênica , Frequência do Gene , Genótipo , Alemanha , Antígenos HLA-DQ/genética , Cadeias alfa de HLA-DQ , Cadeias beta de HLA-DQ , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores CXCR3/genética , Receptores CXCR3/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
TIM-3 is a transmembrane protein preferentially expressed on differentiated Th1 cells, which play a role in Th1-mediated diseases including type 1 diabetes. We investigated the role of the rs10515746 (A/C), rs1036199 (A/C), and rs10053538 (A/C) single nucleotide polymorphisms (SNPs) within the TIM-3 gene in 186 German type 1 diabetes families (558 individuals) and its interaction with human leukocyte antigen (HLA) high-risk haplotypes DQ2(DQA*0501-DQB*0201)-DQ8 (DQA*0301-DQB*0302). Alleles A, C, and A of the rs10515746 (A/C), rs1036199 (A/C), and rs10053538 (A/C) SNPs were found in a frequency of 20.4%, 19.0%, and 4.2%, respectively. Transmission analysis of these polymorphisms did not show any significant difference. Although in patients with HLA DQx/x (neither HLA DQ2 nor DQ8) an undertransmission of allele A (14.3% vs. 85.7%) of the rs10053538 (A/C) SNP and an overtransmission of allele A (66.7% vs. 33.3%) of the rs10515746 (A/C) SNP was observed, these associations did not remain statistically significant after correction for multiple comparisons. Although we found no association of TIM-3 with type 1 diabetes in the German population, we cannot discard a possible association in a larger size.
