Endocrine Abstracts

Introduction: Viral pathogens seem to play a role in triggering the autoimmune destruction that leads to type 1 diabetes mellitus (T1DM) development. Toll-like receptor 3 (TLR3) has been shown to recognize double-stranded RNA, a molecular signature of most viruses. It is expressed at high levels in pancreatic beta-cells and immune cells, suggesting a role for it in the T1DM pathogenesis. Therefore, the aim of this study was investigate if TLR3 polymorphisms are associated with T1DM.

Methods: Frequencies of the TLR3 rs11721827, rs13126816, rs5743313, rs7668666 and rs3775291 polymorphisms were analyzed in 449 T1DM patients and in 507 non-diabetic subjects from South Brazil. Linkage disequilibrium (LD) among TLR3 polymorphisms were calculated using |D’| and r² measurements. Haplotypes constructed from the combination of these polymorphisms were inferred by using a Bayesian statistical method.

Results: Any significant LD was found between all pairs of combination of the five analyzed polymorphisms. The rs3775291G and rs13126816G alleles were more frequent in T1DM patients than in nondiabetic subjects (rs3775291: 0.73 vs 0.67 (P=0.0001); rs13126816: 0.70 vs 0.62 (P=0.001)). These associations were stronger for the additive model of inheritance (rs3775291: OR=2.3 (95% CI 1.3–4.2); rs13126816: OR=2.1 (95% CI 1.3–3.1)). Interestingly, the frequency of T1DM was higher as more risk alleles of the five polymorphisms were present in the haplotype (P-trend=0.001). Moreover, in T1DM patients, the minor alleles of the rs5743313 and rs117221827 polymorphisms were associated with an early age at diagnosis and worse glycemic control (P<0.05).

Conclusion: The TLR3 rs3775291 and rs13126816 polymorphisms are associated with risk for developing T1DM, while the rs5743313 and rs11721827 polymorphisms are associated with an early age at T1DM diagnosis and worst glycemic control. The number of risk alleles of the TLR3 polymorphisms in the haplotypes seems to influence the risk for T1DM, suggesting that these polymorphisms might interact in the susceptibility for the disease.