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Diabetes 52:568-572, 2003
© 2003 by the American Diabetes Association, Inc.

Brief Genetics Reports

Large-Scale Association Studies of Variants in Genes Encoding the Pancreatic ß-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. McCarthy6,7, Andrew T. Hattersley1, and Timothy M. Frayling1

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


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