Endocrine Abstracts

Introduction: Polymorphisms in genes that encode proteins of the innate immune system, such as the toll-like receptor 4 (TLR4), could affect the immune response as well as the prevalence of type 2 diabetes mellitus (T2DM). Activated TLR4 induces expression of a spectrum of proinflammatory cytokines, which have been implicated in insulin resistance. Some studies have reported associations of the TLR4 Asp299Gly and Thr399Ile polymorphisms with T2DM. However, other studies have failed to confirm the associations. Thus, this paper describes a case-control study and a meta-analysis conducted to attempt to determine if these two TLR4 polymorphisms are associated with T2DM.

Methods: The case-control study enrolled 1,683 T2DM patients and 584 non-diabetic subjects from Brazil. A literature search was conducted in order to identify studies that investigated associations between the referred TLR4 polymorphisms and T2DM. Pooled odds ratios (OR) were calculated for allele contrast and dominant inheritance models.

Results: In the case-control study, genotype and allele frequencies of the Asp299Gly and Thr399Ile polymorphisms differed between T2DM patients and non-diabetic subjects (P<0.05). Moreover, the presence of the minor alleles of these polymorphisms were significantly associated with protection for T2DM, after adjusting for ethnicity, under a dominant model (Asp299Gly: OR=0.68 (95% CI 0.49–0.94); Thr399Ile: OR=0.65 (95% CI 0.46–0.90)). Seven studies were eligible for inclusion in the meta-analysis. Meta-analysis results showed that the Asp299Gly polymorphism was associated with T2DM protection (OR=0.68 (95% CI 0.46–1.00), allele contrast model). Stratification by ethnicity revealed that both polymorphisms were associated with T2DM protection under allele contrast and dominant models in Brazilian population but not in Europeans.

Conclusions: In our case-control study, we were able to demonstrate a possible association between the TLR4 Asp299Gly and Thr399Ile polymorphisms and protection for T2DM. In agreement, our meta-analysis detected a significant association between the 299Gly allele and T2DM protection.