Association and Haplotype Analysis of the Insulin-Degrading Enzyme (IDE) Gene, a Strong Positional and Biological Candidate for Type 2 Diabetes Susceptibility
- Christopher J. Groves12,
- Steven Wiltshire23,
- Damian Smedley3,
- Katherine R. Owen4,
- Timothy M. Frayling4,
- Mark Walker5,
- Graham A. Hitman6,
- Jonathan C. Levy1,
- Stephen O’Rahilly7,
- Stephan Menzel2,
- Andrew T. Hattersley4 and
- Mark I. McCarthy123
- 1Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, U.K.
- 2Wellcome Trust Centre for Human Genetics, Oxford, U.K.
- 3Genetics and Genomics Research Institute, Imperial College Faculty of Medicine, Hammersmith Hospital, London, U.K.
- 4Centre for Molecular Genetics, Peninsular Medical School, Exeter, U.K.
- 5School of Clinical Medical Sciences, University of Newcastle, Newcastle, U.K.
- 6Department of Diabetes and Metabolic Medicine, Bart’s and the London Queen Mary’s School of Medicine and Dentistry, London, U.K.
- 7Departments 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.
Footnotes
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Address correspondence and reprint requests to Prof. Mark McCarthy, Robert Turner Professor of Diabetes, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Site, Old Road, Headington, Oxford OX3 7LJ, U.K. E-mail: mark.mccarthy{at}drl.ox.ac.uk.
Received for publication 5 November 2002 and accepted in revised form 10 February 2003.
Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org.
CON, control; DIF, Diabetes in Families Study; ECACC, European Collection of Cell Cultures; HAP, haplotype; IDE, insulin-degrading enzyme; LOD, logarithm of odds; NCBI, National Center for Biotechnology Information; NPL, nonparametric linkage; OR, odds ratio; SNP, single nucleotide polymorphism; UTR, untranslated region; W2P, Warren 2 probands; W2T, Warren 2 trios; YT2D, young type 2 diabetes.
- DIABETES
