High-Density Haplotype Structure and Association Testing of the Insulin-Degrading Enzyme (IDE) Gene With Type 2 Diabetes in 4,206 People
- Jose C. Florez1234,
- Steven Wiltshire5,
- Christina M. Agapakis13,
- Noël P. Burtt3,
- Paul I.W. de Bakker136,
- Peter Almgren7,
- Kristina Bengtsson Boström8,
- Tiinamaija Tuomi9,
- Daniel Gaudet10,
- Mark J. Daly23,
- Joel N. Hirschhorn3611,
- Mark I. McCarthy512,
- David Altshuler12346 and
- Leif Groop7
- 1Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
- 2Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
- 3Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
- 4Department of Medicine, Harvard Medical School, Boston, Massachusetts
- 5Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K
- 6Department of Genetics, Harvard Medical School, Boston, Massachusetts
- 7Department of Endocrinology, University Hospital MAS, Lund University, Malmö, Sweden
- 8Department of Clinical Science, University Hospital MAS, Lund University, Malmö, Sweden
- 9Department of Medicine, Helsinki University Central Hospital; Folkhalsan Genetic Institute, Folkhalsan Research Center, and Research Program for Molecular Medicine, University of Helsinki, Helsinki, Finland
- 10Chicoutimi Hospital, University of Montreal Community Genomic Center, Quebec, Canada
- 11Divisions of Genetics and Endocrinology, Children’s Hospital, Boston, Massachusetts
- 12Oxford 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
Abstract
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.
- 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
Footnotes
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D.A. and L.G. jointly supervised this project.
L.G. has been a member of an advisory board for and has received consulting fees from Aventis-Sanofi, Bristol-Myers Squibb, Kowa, and Roche.
Additional information for this article can be found in an online appendix available at http://diabetes.diabetesjournals.org.
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- Accepted October 4, 2005.
- Received July 26, 2005.
- DIABETES
