The effects of TLR3, TRIF and TRAF3 SNPs and interactions with environmental factors on type 2 diabetes mellitus and vascular complications in a Han Chinese population

Toll-like receptor 3 (TLR3) is involved in type I interferon-β (IFN-β) via TIR-domain-containing adapter-inducing interferon-β (TRIF) and Tumor necrosis factor receptor-associated factor 3 (TRAF3), culminating in inflammation and immunity reactions. TLR3 is implicated in insulin resistance and type 2 diabetes mellitus (T2DM). Eight SNPs of these genes were detected in 552 T2DM patients and 552 matched healthy control subjects. Gene-gene and gene-environment interactions and haplotype associations were also evaluated. We identified a 21% increased risk of T2DM for the T allele of rs12435483 in the TRAF3 gene (OR: 1.21; 95% CI: 1.01-1.44; P = 0.036). The GA genotype and GA + AA genotype of TRAF3 rs12147254 were found to increase the risk of coronary heart disease (CHD) among T2DM patients (GA vs. GG: OR = 4.17, 95% CI: 1.04-16.79, P = 0.045; GA + AA vs. GG: OR = 3.97, 95% CI: 1.02-15.48, P = 0.047). However, the GACGAC haplotype in TRAF3 had a protective effect on T2DM micro-macrovascular complications (OR = 0.33, 95% CI: 0.13-0.85, P = 0.017). Two-factor (TRAF3 rs12435483 and LDL) and three-factor (TRAF3 rs12435483, BMI and HDL) interactions of the risk of T2DM were identified. In conclusion, the genetic variants in the TLR3-TRIF-TRAF3-INF-β signaling pathway and interactions with some particular environmental factors (LDL, BMI and HDL) may contribute to susceptibility to T2DM and vascular complications in the Han Chinese population.