Endocrine Abstracts

Background and Aims: Type 1 diabetes mellitus (T1DM) is caused by an autoimmune destruction of pancreatic beta cells, which renders patients insulin-dependent for life. The disease arises from a complex interaction among several genetic and environmental factors. To date, single nucleotide polymorphisms (SNPs) in >50 genes have been associated with T1DM, with HLA class II SNPs having the greatest impact on disease susceptibility. Other loci have minor effects on T1DM risk; however, the combination of HLA genotypes and non-HLA SNPs has been shown to improve disease prediction. Therefore, the identification of new non-HLA SNPs associated with T1DM might aid disease prediction. In this context, tyrosine kinase 2 (TYK2) is a new candidate gene for T1DM since it plays an important role in regulating apoptotic and proinflammatory pathways in beta cells through modulation of IFNα signaling. Accordingly, SNPs in TYK2 gene have been associated with protection for autoimmune diseases. Thus, the aim of the present study was to investigate the association between a nonsynonymous SNP (rs2304256) in TIK2 gene and T1DM in a Brazilian population.

Methods: This case-control study comprised 478 patients with T1DM (cases) and 522 non-diabetic subjects (controls) from Porto Alegre (Rio Grande do Sul, Brazil). The rs2304256 (C/A) SNP was genotyped by allele discrimination-real time PCR technique using TaqMan MGB probes (Thermo Fisher Scientific). In addition, HLA class II DR/DQ genotypes associated with high risk for T1DM were genotyped to control a possible association of the TYK2 rs2304256 SNP with T1DM for these HLA genotypes.

Results: Genotype frequencies of the rs2304256 SNP differed significantly between T1DM patients and non-diabetic subjects (T1DM: C/C 59.4%, C/A 34.3%, A/A 6.3% vs. Controls: C/C 54.6%, C/A 32.2%, A/A 13.2%; P=0.001). The frequency of the minor allele (A) was 23% in T1DM group and 29% in control subjects, and this allele was significantly associated with T1DM protection under a dominant model of inheritance, adjusting for HLA high-risk genotypes, body mass index, ethnicity and hypertension (OR=0.60, 95% CI 0.39 – 0.95, P=0.025).

Conclusions: Our results demonstrated that the TYK2 rs2304256 A allele is associated with protection for T1DM in a Brazilian population. No previous study has evaluated this SNP in Brazil.