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High-Density Haplotype Structure and Association Testing of the Insulin-Degrading Enzyme (IDE) Gene With Type 2 Diabetes in 4,206 People

¹ Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
² Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
³ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
⁴ Department of Medicine, Harvard Medical School, Boston, Massachusetts
⁵ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K
⁶ Department of Genetics, Harvard Medical School, Boston, Massachusetts
⁷ Department of Endocrinology, University Hospital MAS, Lund University, Malmö, Sweden
⁸ Department of Clinical Science, University Hospital MAS, Lund University, Malmö, Sweden
⁹ Department of Medicine, Helsinki University Central Hospital; Folkhalsan Genetic Institute, Folkhalsan Research Center, and Research Program for Molecular Medicine, University of Helsinki, Helsinki, Finland
¹⁰ Chicoutimi Hospital, University of Montreal Community Genomic Center, Quebec, Canada
¹¹ Divisions of Genetics and Endocrinology, Children’s Hospital, Boston, Massachusetts
¹² Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford, U.K

Address correspondence and reprint requests to Jose C. Florez, Diabetes Unit, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114. E-mail: jcflorez{at}partners.org

Abbreviations: AUC, area under the curve; CEPH, Centre d’Etude du Polymorphisme Humain; HOMA-IR, homeostasis model assessment of insulin resistance; IDE, insulin-degrading enzyme; SNP, single nucleotide polymorphism

The insulin-degrading enzyme is responsible for the intracellular proteolysis of insulin. Its gene IDE is located on chromosome 10, in an area with suggestive linkage to type 2 diabetes and related phenotypes. Due to the impact of genetic variants of this gene in rodents and the function of its protein product, it has been proposed as a candidate gene for type 2 diabetes. Various groups have explored the role of the common genetic variation of IDE on insulin resistance and reported associations of various single nucleotide polymorphisms (SNPs) and haplotypes on both type 2 diabetes and glycemic traits. We sought to characterize the haplotype structure of IDE in detail and replicate the association of common variants with type 2 diabetes, fasting insulin, fasting glucose, and insulin resistance. We assessed linkage disequilibrium, selected single-marker and multimarker tags, and genotyped these markers in several case-control and family-based samples totalling 4,206 Caucasian individuals. We observed no statistically significant evidence of association between single-marker or multimarker tests in IDE and type 2 diabetes. Nominally significant differences in quantitative traits are consistent with statistical noise. We conclude that common genetic variation at IDE is unlikely to confer clinically significant risk of type 2 diabetes in Caucasians.

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