Brief Genetics Report Association and Haplotype Analysis of the Insulin-Degrading Enzyme (IDE) Gene, a Strong Positional and Biological Candidate for Type 2 Diabetes Susceptibility Christopher J. Groves, 1,2 Steven Wiltshire, 2,3 Damian Smedley, 3 Katherine R. Owen, 4 Timothy M. Frayling, 4 Mark Walker, 5 Graham A. Hitman, 6 Jonathan C. Levy, 1 Stephen O’Rahilly, 7 Stephan Menzel, 2 Andrew T. Hattersley, 4 and Mark I. McCarthy 1,2,3 The gene for insulin-degrading enzyme (IDE) repre- sents a strong positional and biological candidate for type 2 diabetes susceptibility. IDE maps to chromosome 10q23.3, a region linked to diabetes in several popula- tions; 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 hap- lotype 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 associa- tions, although one variant (IDE2, 179T3 C) showed modest association with diabetes (odds ratio [OR]1.25, P  0.03). Linkage partitioning analyses failed to sup- port this association, but provided borderline evidence for a different variant (IDE10, IVS20–405A3 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. Diabetes 52:1300 –1305, 2003 L inkage disequilibrium analysis within candidate genes represents the final common pathway for the identification of diabetes-susceptibility genes. Candidate selection is typically based on posi- tional information from linkage studies in humans and rodent models and/or a perceived match between the gene’s function and the pathophysiology of the condition. Several independent lines of evidence suggest a role for the gene encoding the insulin-degrading enzyme (IDE: LOCUSLINK reference 3416; EC reference 3.4.24.56) in type 2 diabetes pathogenesis, making this a promising candidate for analysis. First, IDE maps to a region, on chromosome 10q, showing evidence for linkage to type 2 diabetes in several populations. In a genomewide scan of 573 U.K. type 2 diabetic pedigrees, evidence for linkage (multipoint logarithm of odds [LOD] = 1.99) peaked near to D10S1765, only 4 Mb from IDE, and conditional analy- ses have suggested epistatic interaction with the well- replicated susceptibility locus on chromosome 1q (1). Linkage to 10q has also been reported in Finns (2), North American Europeans (3), Mexican Americans (4), and French (5), though the latter two map 40 –50 cM telomeric and may reflect a distinct locus. Second, the rat homolog of IDE is directly implicated in type 2 diabetes susceptibility. In the GK rat model (6,7), a locus for poststimulation glycemia was mapped to a region of rat chromosome 1 syntenic with human 10q23-26 (8,9) and subsequently localized to a 1-cM region around Ide (10). Two amino-acid substitutions in Ide were found in susceptible congenic strains, which, together, conferred postprandial hyperglycemia and reduced insulin degrada- tion in isolated muscle cells, and other diabetes-related phenotypes (10). Third, the known and presumed functions of IDE are From the 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 Genet- ics, Peninsular Medical School, Exeter, U.K.; 5 School of Clinical Medical Sciences, University of Newcastle, Newcastle, U.K.; the 6 Department of Diabetes and Metabolic Medicine, Bart’s and the London Queen Mary’s School of Medicine and Dentistry, London, U.K.; and the 7 Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, U.K. Address correspondence and reprint requests to Prof. Mark McCarthy, Robert Turner Professor of Diabetes, Oxford Centre for Diabetes, Endocri- nology and Metabolism, Churchill Site, Old Road, Headington, Oxford OX3 7LJ, U.K. E-mail: mark.mccarthy@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 Collec- tion 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. © 2003 by the American Diabetes Association. 1300 DIABETES, VOL. 52, MAY 2003