PLoS ONE (Jan 2012)

Common variants in the type 2 diabetes KCNQ1 gene are associated with impairments in insulin secretion during hyperglycaemic glucose clamp.

  • Jana V van Vliet-Ostaptchouk,
  • Timon W van Haeften,
  • Gijs W D Landman,
  • Erwin Reiling,
  • Nanne Kleefstra,
  • Henk J G Bilo,
  • Olaf H Klungel,
  • Anthonius de Boer,
  • Cleo C van Diemen,
  • Cisca Wijmenga,
  • H Marike Boezen,
  • Jacqueline M Dekker,
  • Esther van 't Riet,
  • Giel Nijpels,
  • Laura M C Welschen,
  • Hata Zavrelova,
  • Elinda J Bruin,
  • Clara C Elbers,
  • Florianne Bauer,
  • N Charlotte Onland-Moret,
  • Yvonne T van der Schouw,
  • Diederick E Grobbee,
  • Annemieke M W Spijkerman,
  • Daphne L van der A,
  • Annemarie M Simonis-Bik,
  • Elisabeth M W Eekhoff,
  • Michaela Diamant,
  • Mark H H Kramer,
  • Dorret I Boomsma,
  • Eco J de Geus,
  • Gonneke Willemsen,
  • P Eline Slagboom,
  • Marten H Hofker,
  • Leen M 't Hart

DOI
https://doi.org/10.1371/journal.pone.0032148
Journal volume & issue
Vol. 7, no. 3
p. e32148

Abstract

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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.