OBJECTIVE - Two independent genome-wide association studies for type 2 diabetes in Japanese subjects have recently identified common variants in the KCNQ1 gene that are strongly associated with type 2 diabetes. Here we studied whether a common variant in KCNQ1 would influence BMI as well as insulin secretion and action and predict future type 2 diabetes in subjects from Sweden and Finland. RESEARCH DESIGN AND METHODS - Risk of type 2 diabetes conferred by KCNQ1 rs2237895 was studied in 2,830 type 2 diabetic case subjects and 3,550 control subjects from Sweden (MalmöCase-Control) and prospectively in 16,061 individuals from the MalmöPreventive Project (MPP). Association between genotype and insulin secretion/action was assessed cross-sectionally in 3,298 nondiabetic subjects from the Prevalence, Prediction and Prevention of Diabetes (PPP)-Botnia Study and longitudinally in 2,328 nondiabetic subjects from the Botnia Prospective Study (BPS). KCNQ1 expression (n = 18) and glucose-stimulated insulin secretion (n = 19) were measured in human islets from nondiabetic cadaver donors. RESULTS - The C-allele of KCNQ1 rs2237895 was associated with increased risk of type 2 diabetes in both the Malmö Case-Control (odds ratio 1.23 [95% CI 1.12-1.34]; P = 5.6 × 10 -6) and the prospective (1.14 [1.06 -1.22]; P = 4.8 × 10 -4) studies. Furthermore, the C-allele was associated with decreased insulin secretion (corrected insulin response [CIR] P = 0.013; disposition index [DI] P = 0.013) in the PPP-Botnia Study and in the BPS at baseline (CIR P = 3.6 × 10-4; DI P = 0.0058) and after follow-up (CIR P = 0.0018; DI P = 0.0030). C-allele carriers showed reduced glucose-stimulated insulin secretion in human islets (P = 2.5 × 10-6). CONCLUSIONS - A common variant in the KCNQ1 gene is associated with increased risk of future type 2 diabetes in Scandinavians, which partially can be explained by an effect on insulin secretion. © 2009 by the American Diabetes Association.
CITATION STYLE
Jonsson, A., Isomaa, B., Tuomi, T., Taneera, J., Salehi, A., Nilsson, P., … Lyssenko, V. (2009). A variant in the KCNQ1 gene predicts future type 2 diabetes and mediates impaired insulin secretion. Diabetes, 58(10), 2409–2413. https://doi.org/10.2337/db09-0246
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