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This version published online on November 23, 2004
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1212
A more recent version of this article appeared on February 1, 2005
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Submitted on June 24, 2004
Accepted on November 10, 2004

The Insulin Gene Variable Number Tandem Repeat and Risk of Type 2 Diabetes in a Population-Based Sample of Families and Unrelated Men and Women

James B. Meigs MD, MPH*, Josée Dupuis PhD, Alan G. Herbert MBChB, PhD, Chunyu Liu, Peter W.F. Wilson MD, and L. Adrienne Cupples PhD

General Internal Medicine and Clinical Epidemiology Units, General Medicine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Department of Biostatistics, Boston University School of Public Health, Boston, MA; Framingham Heart Study Genetics Laboratory, Department of Neurology, Boston University School of Medicine, Boston, MA; Framingham Heart Study, Framingham, MA, and Boston University School of Medicine, Boston, MA

* To whom correspondence should be addressed.
James B. Meigs, E-mail: jmeigs{at}partners.org

Abnormalities in insulin regulation are central to the pathogenesis of type 2 diabetes. We assessed variation in the insulin gene variable number tandem repeat (INS VNTR) minisatellite (using the -23Hph1 A/T SNP) as a risk factor for 92 cases of incident type 2 diabetes in 883 unrelated Framingham Heart Study (FHS) subjects and in a separate sample of 698 members of 282 FHS nuclear families with 62 diabetes cases. In the unrelated sample the -23Hph1 TT genotype frequency was 8.0% and was associated with a diabetes hazard ratio of 1.89 (95% confidence interval 1.01-3.52, P = 0.045) compared with the AA genotype using diabetes age-of-onset as the time failure variable in a proportional hazards model adjusted for age, offspring sex, BMI, parental diabetes, and sex-by-parental diabetes interactions. In sex-stratified analyses TT increased risk for diabetes in women (HR 4.25, 95% CI 1. 76-10.3) but not men (HR 1.01, 0.39-2.60). Using a family-based association test to assess transmission disequilibrium in the sample of related subjects, the age and sex-adjusted Z score for diabetes associated with the T allele was 2.07 (P = 0.04), and a family-based association test using age-of-onset in a proportional hazards model was also statistically significant (P = 0.03), indicating that increased risk of diabetes was not attributable to population admixture. These data support the hypothesis that the INS VNTR is a genetic risk factor for type 2 diabetes, with the TT genotype accounting for about 6.6% of cases in the FHS population.
Key words: type 2 diabetes mellitus • insulin • genetics • risk factors • longitudinal study




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