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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

General Internal Medicine and Clinical Epidemiology Units, General Medicine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School (J.B.M.), Boston, Massachusetts 02114; Department of Biostatistics, Boston University School of Public Health (J.D., L.A.C.), Boston, Massachusetts 02118; Framingham Heart Study Genetics Laboratory, Department of Neurology, Boston University School of Medicine (A.G.H., C.L., P.W.F.W.), Boston, Massachusetts 02118; and Framingham Heart Study (P.W.F.W.), Framingham, Massachusetts 01702

Address all correspondence and requests for reprints to: Dr. James B. Meigs, General Medicine Division, Massachusetts General Hospital, 9th Floor, 50 Staniford Street, Boston, Massachusetts 02114. 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 single nucleotide polymorphism) 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 (CI), 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, body mass index, parental diabetes, and sex by parental diabetes interactions. In sex-stratified analyses, TT increased risk for diabetes in women (hazard ratio, 4.25; 95% CI, 1.76–10.3), but not men (hazard ratio, 1.01; 95% CI, 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.

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