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

J Clin Endocrinol Metab. 2005 Feb;90(2):1137-43. doi: 10.1210/jc.2004-1212. Epub 2004 Nov 23.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Body Mass Index
  • Diabetes Mellitus, Type 2 / epidemiology
  • Diabetes Mellitus, Type 2 / genetics*
  • Family
  • Female
  • Follow-Up Studies
  • Humans
  • Incidence
  • Insulin / genetics*
  • Male
  • Middle Aged
  • Minisatellite Repeats / genetics*
  • Phenotype
  • Polymorphism, Genetic
  • Risk Factors


  • Insulin