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

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...

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Published in:PloS one 2012-03, Vol.7 (3), p.e32148-e32148
Main Authors: van Vliet-Ostaptchouk, Jana V, van Haeften, Timon W, Landman, Gijs W D, Reiling, Erwin, Kleefstra, Nanne, Bilo, Henk J G, Klungel, Olaf H, de Boer, Anthonius, van Diemen, Cleo C, Wijmenga, Cisca, Boezen, H Marike, Dekker, Jacqueline M, van 't Riet, Esther, Nijpels, Giel, Welschen, Laura M C, Zavrelova, Hata, Bruin, Elinda J, Elbers, Clara C, Bauer, Florianne, Onland-Moret, N Charlotte, van der Schouw, Yvonne T, Grobbee, Diederick E, Spijkerman, Annemieke M W, van der A, Daphne L, Simonis-Bik, Annemarie M, Eekhoff, Elisabeth M W, Diamant, Michaela, Kramer, Mark H H, Boomsma, Dorret I, de Geus, Eco J, Willemsen, Gonneke, Slagboom, P Eline, Hofker, Marten H, 't Hart, Leen M
Format: Article
Language:English
Subjects:
Alleles
Bioinformatics
Biology
Case-Control Studies
Cholesterol
Complications
Data processing
Diabetes
Diabetes Complications - genetics
Diabetes mellitus
Diabetes Mellitus, Type 2 - genetics
Diabetes Mellitus, Type 2 - metabolism
Diabetes Mellitus, Type 2 - mortality
Diabetes Mellitus, Type 2 - physiopathology
Diabetes therapy
Diabetic retinopathy
Diabetics
Epidemiology
Female
Gene loci
Genes
Genetic aspects
Genetic Predisposition to Disease - genetics
Genetics
Genome-wide association studies
Genomes
Genotypes
Glucose
Glucose Clamp Technique
Health sciences
Hemoglobin
Humans
Hyperglycemia
Hyperglycemia - metabolism
Insulin
Insulin - metabolism
Insulin Secretion
Internal medicine
KCNQ1 Potassium Channel - genetics
KCNQ1 protein
Lipid metabolism
Lipoproteins (low density)
Low density lipoprotein
Male
Medical statistics
Medicine
Metabolism
Middle Aged
Nephropathy
Pathology
Patients
Pharmaceutical sciences
Physicians
Physiological aspects
Physiology
Polymorphism, Single Nucleotide
Population studies
Potassium channels (voltage-gated)
Primary care
Public health
Retinopathy
Risk
Rodents
Secretion
Studies
Type 2 diabetes
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Summary: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. 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. 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. 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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0032148