Association between variations in the TLR4 gene and incident type 2 diabetes is modified by the ratio of total cholesterol to HDL-cholesterol

Background: Toll-like receptor 4 (TLR4), the signaling receptor for
lipopolysaccharides, is an important member of the innate immunity
system. Since several studies have suggested that type 2 diabetes
might be associated with changes in the innate immune response, we
sought to investigate the association between genetic variants in
the TLR4 gene and incident type 2 diabetes. Methods: A case-cohort
study was conducted in initially healthy, middle-aged subjects from
the MONICA/KORA Augsburg studies including 498 individuals with
incident type 2 diabetes and 1,569 noncases. Seven SNPs were
systematically selected in the TLR4 gene and haplotypes were
reconstructed. Results: The effect of TLR4 SNPs on incident type 2
diabetes was modified by the ratio of total cholesterol to high-
density lipoprotein cholesterol (TC/HDL-C). In men, four out of
seven TLR4 variants showed significant interaction with TC/HDL-C
after correction for multiple testing (p < 0.01). The influence
of the minor alleles of those variants on the incidence of type 2
diabetes was observed particularly for male patients with high
values of TC/HDL-C. Consistent with these findings, haplotype-based
analyses also revealed that the effect of two haplotypes on
incident type 2 diabetes was modified by TC/HDL-C in men (p <
10(-3)). However, none of the investigated variants or haplotypes
was associated with type 2 diabetes in main effect models without
assessment of effect modifications. Conclusion: We conclude that
minor alleles of several TLR4 variants, although not directly
associated with type 2 diabetes might increase the risk for type 2
diabetes in subjects with high TC/HDL-C. Additionally, our results
confirm previous studies reporting sex-related dissimilarities in
the development of type 2 diabetes.