title: Common variants in the type 2 diabetes KCNQ1 gene are associated with impairments in insulin secretion during hyperglycaemic glucose clamp.
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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
authors.affiliation: Molecular Genetics, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. j.v.van.vliet@umcg.nl
authors.forename: Jana V
authors.initials: JV
authors.lastname: van Vliet-Ostaptchouk
authors.forename: Timon W
authors.initials: TW
authors.lastname: van Haeften
authors.forename: Gijs W D
authors.initials: GW
authors.lastname: Landman
authors.forename: Erwin
authors.initials: E
authors.lastname: Reiling
authors.forename: Nanne
authors.initials: N
authors.lastname: Kleefstra
authors.forename: Henk J G
authors.initials: HJ
authors.lastname: Bilo
authors.forename: Olaf H
authors.initials: OH
authors.lastname: Klungel
authors.forename: Anthonius
authors.initials: A
authors.lastname: de Boer
authors.forename: Cleo C
authors.initials: CC
authors.lastname: van Diemen
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.forename: H Marike
authors.initials: HM
authors.lastname: Boezen
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Dekker
authors.forename: Esther
authors.initials: E
authors.lastname: van 't Riet
authors.forename: Giel
authors.initials: G
authors.lastname: Nijpels
authors.forename: Laura M C
authors.initials: LM
authors.lastname: Welschen
authors.forename: Hata
authors.initials: H
authors.lastname: Zavrelova
authors.forename: Elinda J
authors.initials: EJ
authors.lastname: Bruin
authors.forename: Clara C
authors.initials: CC
authors.lastname: Elbers
authors.forename: Florianne
authors.initials: F
authors.lastname: Bauer
authors.forename: N Charlotte
authors.initials: NC
authors.lastname: Onland-Moret
authors.forename: Yvonne T
authors.initials: YT
authors.lastname: van der Schouw
authors.forename: Diederick E
authors.initials: DE
authors.lastname: Grobbee
authors.forename: Annemieke M W
authors.initials: AM
authors.lastname: Spijkerman
authors.forename: Daphne L
authors.initials: DL
authors.lastname: van der A
authors.forename: Annemarie M
authors.initials: AM
authors.lastname: Simonis-Bik
authors.forename: Elisabeth M W
authors.initials: EM
authors.lastname: Eekhoff
authors.forename: Michaela
authors.initials: M
authors.lastname: Diamant
authors.forename: Mark H H
authors.initials: MH
authors.lastname: Kramer
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.forename: Eco J
authors.initials: EJ
authors.lastname: de Geus
authors.forename: Gonneke
authors.initials: G
authors.lastname: Willemsen
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.forename: Marten H
authors.initials: MH
authors.lastname: Hofker
authors.forename: Leen M
authors.initials: LM
authors.lastname: 't Hart
mesh_terms: D016022:Case-Control Studies; D048909:Diabetes Complications / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D015309:Glucose Clamp Technique; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: D007328:Insulin; D051657:KCNQ1 Potassium Channel