Large-Scale Association Studies of Variants in Genes Encoding the Pancreatic β-Cell KATP Channel Subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) Confirm That the KCNJ11 E23K Variant Is Associated With Type 2 Diabetes

Anna L. Gloyn; Michael N. Weedon; Katharine R. Owen; Martina J. Turner; Bridget A. Knight; Graham Hitman; Mark Walker; Jonathan C. Levy; Mike Sampson; Stephanie Halford; Mark I. McCarthy; Andrew T. Hattersley; Timothy M. Frayling

doi:10.2337/diabetes.52.2.568

Large-Scale Association Studies of Variants in Genes Encoding the Pancreatic β-Cell K_ATP Channel Subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) Confirm That the KCNJ11 E23K Variant Is Associated With Type 2 Diabetes

¹Centre for Molecular Genetics, Peninsula Medical School, Exeter, U.K.
²Department of Diabetes and Metabolic Medicine, Barts and the London, Queen Mary School of Medicine and Dentistry, University of London, London, U.K.
³Department of Medicine, School of Medicine, Newcastle upon Tyne, U.K.
⁴The Diabetes Research Laboratories, Radcliffe Infirmary, University of Oxford, Oxford, U.K.
⁵Elsie Bertram Diabetes Centre, Norfolk and Norwich, University Hospital, Norwich, U.K.
⁶Imperial College Genetics and Genomics Research Institute and Division of Medicine, Imperial College, London, U.K.
⁷Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.

Abstract

The genes ABCC8 and KCNJ11, which encode the subunits sulfonylurea receptor 1 (SUR1) and inwardly rectifying potassium channel (Kir6.2) of the β-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 (∼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.

Footnotes

Address correspondence and reprint requests to Professor Andrew T Hattersley, Diabetes and Vascular Medicine, Peninsula Medical School, Barrack Rd., Exeter, EX2 5AX. E-mail: a.t.hattersley{at}exeter.ac.uk.

Received for publication 20 September 2002 and accepted in revised form 5 November 2002.

A.L.G. and M.N.W. contributed equally to this work.

ECACC, European Collection of Cell Cultures; EFS, Exeter Family Study; exon16, exon 16 −3t/c; exon18, exon 18 C/T; HI, hyperinsulinemia of infancy; HWE, Hardy-Weinberg equilibrium; K_ATP channel, ATP-sensitive potassium channel; Kir6.2 channel, inwardly rectifying potassium channel; LD, linkage disequilibrium; OR, odds ratio; SUR1, sulfonylurea receptor 1; TDT, transmission disequilibrium test.
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