Codon 972 polymorphism in the insulin receptor substrate-1 gene, obesity, and risk of noninsulin-dependent diabetes mellitus

J Clin Endocrinol Metab. 1996 Apr;81(4):1657-9. doi: 10.1210/jcem.81.4.8636384.


Because of the role of insulin receptor substrate-1 in insulin action, the insulin receptor substrate-1 gene is a candidate gene for noninsulin-dependent diabetes mellitus (NIDDM). Modest associations between NIDDM and a GGG-->AGG single base substitution (corresponding to a glycine-->arginine amino acid substitution) in codon 972 of the gene have been found, but none reached statistical significance. To examine further how large a proportion of NIDDM cases could be caused by the mutation, we performed a stratified analysis combining the results from the 6 earlier studies and those from our panel of 192 unrelated NIDDM subjects and 104 healthy controls. In addition, we looked for a possibility that the codon 972 mutation plays a role only in the presence of certain conditions. Genomic DNA samples obtained from NIDDM cases and healthy controls were genotyped using a PCR-restriction fragment length polymorphism protocol modified for genomic DNA. The GGG-->AGG substitution was found in 5.7% of the diabetic subjects (11 of 192) and 6.9% of the controls (7 of 104). The difference between groups was not statistically significant, and it was not different from the results of other studies. The Mantel-Haenszel summary odds ratio across all studies was 1.49 (P < 0.05; 95% confidence intervals, 1.01-2.2). This summary odds ratio is consistent with a small proportion of NIDDM cases (approximately 3%) being caused by the mutation. Exploratory subgroup analyses on our panel suggested a clustering of NIDDM, the codon 972 mutation, and overweight, raising the hypothesis that the mutation may predispose to NIDDM only in the presence of excess body weight.

Publication types

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

MeSH terms

  • Adult
  • Base Sequence
  • Body Weight
  • Codon
  • DNA Primers
  • Diabetes Mellitus / epidemiology
  • Diabetes Mellitus / genetics*
  • Diabetes Mellitus, Type 2 / epidemiology*
  • Diabetes Mellitus, Type 2 / genetics*
  • Female
  • Humans
  • Insulin Receptor Substrate Proteins
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Obesity / epidemiology
  • Obesity / genetics*
  • Odds Ratio
  • Phosphoproteins / genetics*
  • Polymerase Chain Reaction
  • Polymorphism, Genetic*
  • Reference Values
  • Risk Factors


  • Codon
  • DNA Primers
  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • Phosphoproteins