Association and Haplotype Analysis of the Insulin-Degrading Enzyme (IDE) Gene, a Strong Positional and Biological Candidate for Type 2 Diabetes Susceptibility
Author:
Groves Christopher J.12, Wiltshire Steven23, Smedley Damian3, Owen Katherine R.4, Frayling Timothy M.4, Walker Mark5, Hitman Graham A.6, Levy Jonathan C.1, O’Rahilly Stephen7, Menzel Stephan2, Hattersley Andrew T.4, McCarthy Mark I.123
Affiliation:
1. Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, U.K. 2. Wellcome Trust Centre for Human Genetics, Oxford, U.K. 3. Genetics and Genomics Research Institute, Imperial College Faculty of Medicine, Hammersmith Hospital, London, U.K. 4. Centre for Molecular Genetics, Peninsular Medical School, Exeter, U.K. 5. School of Clinical Medical Sciences, University of Newcastle, Newcastle, U.K. 6. Department of Diabetes and Metabolic Medicine, Bart’s and the London Queen Mary’s School of Medicine and Dentistry, London, U.K. 7. Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, U.K.
Abstract
The gene for insulin-degrading enzyme (IDE) represents a strong positional and biological candidate for type 2 diabetes susceptibility. IDE maps to chromosome 10q23.3, a region linked to diabetes in several populations; the rat homolog has been directly implicated in diabetes susceptibility; and known functions of IDE support an important role in glucose homeostasis. We sought evidence for association between IDE variation and diabetes by mutation screening, defining local haplotype structure, and genotyping variants delineating common haplotypic diversity. An initial case-control analysis (628 diabetic probands from multiplex sibships and 604 control subjects) found no haplotypic associations, although one variant (IDE2, −179T→C) showed modest association with diabetes (odds ratio [OR]1.25, P = 0.03). Linkage partitioning analyses failed to support this association, but provided borderline evidence for a different variant (IDE10, IVS20–405A→G) (P = 0.06). Neither variant was associated with diabetes when replication was sought in 377 early onset diabetic subjects and 825 control subjects, though combined analysis of all typed cohorts indicated a nominally significant effect at IDE2 (OR 1.21 [1.04–1.40], P = 0.013). In the absence of convincing support for this association from linkage partitioning or analyses of continuous measures of glycemia, we conclude that analysis of over 2,400 samples provides no compelling evidence that variation in IDE contributes to diabetes susceptibility in humans.
Publisher
American Diabetes Association
Subject
Endocrinology, Diabetes and Metabolism,Internal Medicine
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