Codon 972 polymorphism in the insulin receptor substrate-1 gene, obesity, and risk of noninsulin-dependent diabetes mellitus.
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.
Sigal
R J
RJ
Section on Epidemiology and Genetics, Joslin Diabetes Center, Boston, Massachusetts 02215.
Doria
A
A
Warram
J H
JH
Krolewski
A S
AS
D000328:Adult; D001483:Base Sequence; D001835:Body Weight; D003062:Codon; D017931:DNA Primers; D003920:Diabetes Mellitus / Q000453:epidemiology / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009765:Obesity / Q000453:epidemiology / Q000235:genetics*; D016017:Odds Ratio; D010750:Phosphoproteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012016:Reference Values; D012307:Risk Factors
D003062:Codon; D017931:DNA Primers; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins