KCNJ11 variants and their effect on the association between serum potassium and diabetes risk in the Atherosclerosis Risk in Communities (ARIC) Study and Jackson Heart Study (JHS) cohorts

Background In the Atherosclerosis Risk in Communities (ARIC) Study and Jackson Heart Study (JHS) cohorts, serum potassium (K) is an independent predictor of diabetes risk, particularly among African-American participants. Experimental studies show that serum K levels affects insulin secretion. The KCNJ11 gene encodes for a K channel that regulates insulin secretion and whose function is affected by serum K levels. Variants in KCNJ11 are associated with increased diabetes risk. We hypothesized that there could be a gene-by-environment interaction between KCNJ11 variation and serum K on diabetes risk. Methods Evaluating a combined cohort of ARIC and JHS participants, we sought to determine if KCNJ11 variants are risk factors for diabetes; and if KCNJ11 variants modify the association between serum K and diabetes risk. Among participants without diabetes at baseline, we performed multivariable logistic regression to determine the effect of serum K, KCNJ11 variants, and their interactions on the odds of incident diabetes mellitus over 8-9 years in the entire cohort and by race. Results Of 11,812 participants, 3220 (27%) participants developed diabetes. 48% and 47% had 1 or 2 diabetes risk alleles of rs5215 and rs5219, respectively. Caucasians had higher proportions of these risk alleles compared to African Americans (60% vs 17% for rs5215 and 60% vs 13% for rs5219, p<0.01). Serum K was a significant independent predictor of incident diabetes. Neither rs5215 nor rs5219 was associated with incident diabetes. In multivariable models, we found no statistically significant interactions between race and either rs5215 or rs5219 (P-values 0.493 and 0.496, respectively); nor between serum K and either rs5215 or rs5219 on odds of incident diabetes (P-values 0.534 and 0.687, respectively). Conclusion In this cohort, rs5215 and rs5219 of KCNJ11 were not significant predictors of incident diabetes nor effect modifiers of the association between serum K and incident diabetes.