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. Gloyn1,
- Michael N. Weedon1,
- Katharine R. Owen1,
- Martina J. Turner1,
- Bridget A. Knight1,
- Graham Hitman2,
- Mark Walker3,
- Jonathan C. Levy4,
- Mike Sampson5,
- Stephanie Halford6,
- Mark I. McCarthy67,
- Andrew T. Hattersley1 and
- Timothy M. Frayling1
- 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.
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 (KATP) 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.
Address correspondence and reprint requests to Professor Andrew T Hattersley, Diabetes and Vascular Medicine, Peninsula Medical School, Barrack Rd., Exeter, EX2 5AX. E-mail:.
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; KATP 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.