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

J.V. van Vliet-Ostaptchouk, T.W. van Haeften, G.W.D. Landman, E. Reiling, N. Kleefstra, H.J.G. Bilo, O.H. Klungel, A. de Boer, C.C. van Diemen, C. Wijmenga, H.M. Boezen, J.M. Dekker, E. van 't Riet, G. Nijpels, L.M.C. Welschen, H. Zavrelová, E.J. Bruin, C.C. Elbers, F. Bauer, N.C. Onland-MoretY.T. van der Schouw, D.E. Grobbee, A.M.W. Spijkerman, D.L. van der Aa, A.M.C. Bik-Simonis, E.M.W. Eekhoff, M. Diamant, M.H.H. Kramer, D.I. Boomsma, E.J.C. de Geus, G. Willemsen, P.E. Slagboom, M.H. Hofker, L.M. Hart

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Abstract

Background: Genome-wide association studies in Japanese populations recently identified common variants in the KCNQ1 gene to be associated with type 2 diabetes. We examined the association of these variants within KCNQ1 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. Methodology: The KCNQ1 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. Principal Findings: We found that all the genotyped KCNQ1 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, p = 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 (p = 0.025 and 0.0016, respectively). In addition, the risk C-allele of rs2237892 was associated with higher LDL and total cholesterol levels (p = 0.015 and 0.003, respectively). We found no evidence for an association of KCNQ1 with diabetic complications. Conclusions: Common variants in the KCNQ1 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 KCNQ1 is also associated with lipid metabolism. © 2012 van Vliet-Ostaptchouk et al.
Original languageEnglish
Article numbere32148
JournalPLoS ONE
Volume7
Issue number3
DOIs
Publication statusPublished - 2012

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van Vliet-Ostaptchouk, J. V., van Haeften, T. W., Landman, G. W. D., Reiling, E., Kleefstra, N., Bilo, H. J. G., ... Hart, L. M. (2012). Common Variants in the Type 2 Diabetes KCNQ1 Gene Are Associated with Impairments in Insulin Secretion During Hyperglycaemic Glucose Clamp. PLoS ONE, 7(3), [e32148]. https://doi.org/10.1371/journal.pone.0032148