title: Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes.
abstract: The genes ABCC8 and KCNJ11, which encode the subunits sulfonylurea receptor 1 (SUR1) and inwardly rectifying potassium channel (Kir6.2) of the beta-cell ATP-sensitive potassium (K(ATP)) channel, control insulin secretion. Common polymorphisms in these genes (ABCC8 exon 16-3t/c, exon 18 T/C, KCNJ11 E23K) have been variably associated with type 2 diabetes, but no large ( approximately 2,000 subjects) case-control studies have been performed. We evaluated the role of these three variants by studying 2,486 U.K. subjects: 854 with type 2 diabetes, 1,182 population control subjects, and 150 parent-offspring type 2 diabetic trios. The E23K allele was associated with diabetes in the case-control study (odds ratio [OR] 1.18 [95% CI 1.04-1.34], P = 0.01) but did not show familial association with diabetes. Neither the exon 16 nor the exon 18 ABCC8 variants were associated with diabetes (1.04 [0.91-1.18], P = 0.57; 0.93 [0.71-1.23], P = 0.63, respectively). Meta-analysis of all case-control data showed that the E23K allele was associated with type 2 diabetes (K allele OR 1.23 [1.12-1.36], P = 0.000015; KK genotype 1.65 [1.34-2.02], P = 0.000002); but the ABCC8 variants were not associated. Our results confirm that E23K increases risk of type 2 diabetes and show that large-scale association studies are important for the identification of diabetes susceptibility alleles.
authors.affiliation: Centre for Molecular Genetics, Peninsula Medical School, Exeter, UK.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Gloyn
authors.forename: Michael N
authors.initials: MN
authors.lastname: Weedon
authors.forename: Katharine R
authors.initials: KR
authors.lastname: Owen
authors.forename: Martina J
authors.initials: MJ
authors.lastname: Turner
authors.forename: Bridget A
authors.initials: BA
authors.lastname: Knight
authors.forename: Graham
authors.initials: G
authors.lastname: Hitman
authors.forename: Mark
authors.initials: M
authors.lastname: Walker
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Levy
authors.forename: Mike
authors.initials: M
authors.lastname: Sampson
authors.forename: Stephanie
authors.initials: S
authors.lastname: Halford
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005091:Exons; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007515:Islets of Langerhans / Q000502:physiology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors
chemical_list: C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors