Common Variants in the Type 2 Diabetes <em>KCNQ1</em> Gene Are Associated with Impairments in Insulin Secretion During Hyperglycaemic Glucose Clamp

<div><h3>Background</h3><p>Genome-wide association studies in Japanese populations recently identified common variants in the <em>KCNQ1</em> gene to be associated with type 2 diabetes. We examined the association of these variants within <em>KCNQ1</em> with type 2 diabetes in a Dutch population, investigated their effects on insulin secretion and metabolic traits and on the risk of developing complications in type 2 diabetes patients.</p> <h3>Methodology</h3><p>The <em>KCNQ1</em> variants rs151290, rs2237892, and rs2237895 were genotyped in a total of 4620 type 2 diabetes patients and 5285 healthy controls from the Netherlands. Data on macrovascular complications, nephropathy and retinopathy were available in a subset of diabetic patients. Association between genotype and insulin secretion/action was assessed in the additional sample of 335 individuals who underwent a hyperglycaemic clamp.</p> <h3>Principal Findings</h3><p>We found that all the genotyped <em>KCNQ1</em> variants were significantly associated with type 2 diabetes in our Dutch population, and the association of rs151290 was the strongest (OR 1.20, 95% CI 1.07–1.35, <em>p</em> = 0.002). The risk C-allele of rs151290 was nominally associated with reduced first-phase glucose-stimulated insulin secretion, while the non-risk T-allele of rs2237892 was significantly correlated with increased second-phase glucose-stimulated insulin secretion (<em>p</em> = 0.025 and 0.0016, respectively). In addition, the risk C-allele of rs2237892 was associated with higher LDL and total cholesterol levels (<em>p</em> = 0.015 and 0.003, respectively). We found no evidence for an association of <em>KCNQ1</em> with diabetic complications.</p> <h3>Conclusions</h3><p>Common variants in the <em>KCNQ1</em> gene are associated with type 2 diabetes in a Dutch population, which can be explained at least in part by an effect on insulin secretion. Furthermore, our data suggest that <em>KCNQ1</em> is also associated with lipid metabolism.</p>