The Variants in the TCF7L2 Gene Increases the Risk of Type 2 Diabetes in Cuban American by Impairing Glucose Homeostasis (P15-021-19)

Type 2 diabetes (T2D) is a complex and chronic metabolic disorder that involves complex interaction between environmental factors and genetic predisposition. TCF7L2 gene recently emerged as top candidate gene for T2D. Our study is aimed to assess six TCTL2 common polymorphisms: rs7903146, rs12255372, rs11196205, rs7901695, rs7895340 and rs4506565, in relation to T2D and related phenotypes in Cuban Americans who lived in Miami-Dade county, Florida. We conducted a case-control study with 341 Cuban Americans (172 without T2D/169 with T2D). Unconditional logistic regression method was used to assess the association between six TCF7L2 SNPs and the risk of T2D in the additive genetic model, and further adjusted by potential confounding factors such as age, sex, BMI, physical activities and calorie intake. Student's t-tests on continuous values of T2D related quantitative traits were compared between risk allele carriers and non-carriers in control subjects. In addition, linkage disequilibrium and haplotype analysis were performed using Haploview 4.2. Four TCF7L2 SNPs (rs7901695, rs4506565, rs7903146 and rs11225537) were significantly associated with the risk of T2D in a Cuban American population after multivariable adjustment. Among non-diabetic control subjects, risk minor allele carriers of three TCF7L2 SNPs (rs7901695 (T > C), rs4506565 (A > T) and rs7903146 (C > T)) had significantly higher fasting glucose level and marginally higher level of glycated hemoglobin (A1C), compared to non-risk allele carriers. Consistently, results from haplotype analysis showed that two haplotypes TAC and CTT, formed by aforementioned three TCF7L2 SNPs (rs7901695, rs450565 and rs7903146), were significantly associated with the risk of T2D (P = 0.0094, and P = 0.0044, respectively), with the frequency of TAC significantly lower and CTT significantly higher in subjects with T2D, compared to subjects without T2D. The results of this study provide convincing evidence that variation in TCF7L2 genes confers strong susceptibility to T2D in the population studied. Funding for this research was provided through an NIH/NIDDK sponsored grant.