Integrated analysis of probability of type 2 diabetes mellitus with polymorphisms and methylation of KCNQ1 gene: A nested case-control study

Background: To estimate the associations between single-nucleotide polymorphisms (SNPs) and methylation of KCNQ1 gene and type 2 diabetes mellitus (T2DM) risk and the interactions among SNPs, methylation, and environmental factors on T2DM risk.

Methods: We genotyped five SNPs and tested methylation at 39 CpG loci of KCNQ1 in 290 T2DM cases and 290 matched controls nested in the Rural Chinese Cohort Study. Conditional logistic regression model was used to estimate the associations between SNPs and KCNQ1 methylation and T2DM risk. Multifactor dimensionality reduction (MDR) analysis was used to estimate the effect of the interactions SNPs-SNPs, SNPs-methylation, methylation-methylation and SNPs, and methylation-environment on T2DM risk.

Results: Probability of T2DM was decreased with rs2283228 of KCNQ1 (CA vs AA, odds ratio [OR] = 0.65, 95% confidence interval [CI] 0.42-0.99). T2DM probability was significantly increased with rs2237895 combined with hypertriglyceridemia (OR_eg = 2.76, 95% CI 1.35-5.62), with hypertension (OR_eg = 2.23, 95% CI 1.25-3.98), and with body mass index (BMI; OR_eg = 1.93, 95% CI 1.12-3.34). T2DM probability was associated with methylation of CG11 and CG41 (OR = 1.89, 95% CI 1.23-2.89, P = .003). It was significantly associated with the interaction between BMI, hypertriglyceridemia, and CG5 methylation (P = .028 and .028), and the combined effects of CG11 with hypertriglyceridemia and hypertension. On MDR analysis, no significant interaction was observed.

Conclusion: T2DM probability was reduced 35% with rs2283228 polymorphism. It was associated with rs2237895 combined with hypertension, with BMI and with hypertriglyceridemia. The methylation at two CpG loci of KCNQ1 significantly increased T2DM risk by 89%.