TY - JOUR
T1 - Common variants in the type 2 diabetes KCNQ1 gene are associated with impairments in insulin secretion during hyperglycaemic glucose clamp
AU - van Vliet-Ostaptchouk, Jana V
AU - van Haeften, Timon W
AU - Landman, Gijs W D
AU - Reiling, Erwin
AU - Kleefstra, Nanne
AU - Bilo, Henk J G
AU - Klungel, Olaf H
AU - de Boer, Anthonius
AU - van Diemen, Cleo C
AU - Wijmenga, Cisca
AU - Boezen, H Marike
AU - Dekker, Jacqueline M
AU - van 't Riet, Esther
AU - Nijpels, Giel
AU - Welschen, Laura M C
AU - Zavrelova, Hata
AU - Bruin, Elinda J
AU - Elbers, Clara C
AU - Bauer, Florianne
AU - Onland-Moret, N Charlotte
AU - van der Schouw, Yvonne T
AU - Grobbee, Diederick E
AU - Spijkerman, Annemieke M W
AU - van der A, Daphne L
AU - Simonis-Bik, Annemarie M
AU - Eekhoff, Elisabeth M W
AU - Diamant, Michaela
AU - Kramer, Mark H H
AU - Boomsma, Dorret I
AU - de Geus, Eco J
AU - Willemsen, Gonneke
AU - Slagboom, P Eline
AU - Hofker, Marten H
AU - 't Hart, Leen M
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Case-Control Studies
KW - Diabetes Complications
KW - Diabetes Mellitus, Type 2
KW - Female
KW - Genetic Predisposition to Disease
KW - Glucose Clamp Technique
KW - Humans
KW - Hyperglycemia
KW - Insulin
KW - KCNQ1 Potassium Channel
KW - Male
KW - Middle Aged
KW - Polymorphism, Single Nucleotide
U2 - 10.1371/journal.pone.0032148
DO - 10.1371/journal.pone.0032148
M3 - Article
C2 - 22403629
SN - 1932-6203
VL - 7
SP - e32148
JO - PLoS One
JF - PLoS One
IS - 3
ER -
