A common mutation of the insulin receptor substrate-1 gene is a risk factor for coronary artery disease

Insulin resistance is associated with increased risk of atherosclerosis. in sulin receptor substrate-1 (IRS-I) plays a key role in tissue insulin sensi tivity. A common mutation (G972R) of the IRS-1 gene has been shown to impai r IRS-1 function, and it has been associated with reduced insulin sensitivi ty and lipid abnormalities. This led us to investigate the role of the G972 R mutation in predisposing individuals to coronary artery disease (CAD). Th e DNA of 318 subjects with angiographically documented coronary atheroscler osis (>50% stenosis) and 208 population control subjects was analyzed for t he presence of the G972R mutation. This mutation was detected by nested pol ymerase chain reaction and BstNI restriction enzyme digestion. The frequenc y of the G972R mutation was significantly higher among patients with CAD th an controls (18.9% versus 6.8%, respectively; P<0.001). After controlling f or other coronary risk factors, the relative risk of CAD associated with th e G972R mutation was 2.93 (95% CI 1.30 to 6.60; P<0.02) in the entire cohor t. This risk was found to be even higher in the subgroups of obese subjects (odds ratio [OR] 6.97, 95% CI 2.24 to 21.4; P<0.001) and subjects with cli nical features of insulin resistance syndrome (OR 27.3, 95% CI 7.19 to 104. 0; P<0.001). The IRS-1 gene variant was associated with a higher frequency of diabetes mellitus (14.9% among, carriers versus 6.5% among noncarriers; P<0.01) and with a 60% increase of plasma total triglycerides (P<0.001), Al so, plasma concentrations of total cholesterol and the ratio of total chole sterol to HDL cholesterol were significantly (P<0.001) higher among carrier s than noncarriers, although to lesser a extent, These effects were indepen dent of CAD status. The G972R mutation in the IRS-1 gene was found to be a significant independent predictor of CAD. Moreover, this mutation greatly i ncreased the risk of CAD in obese subjects and in patients with the cluster of abnormalities of insulin resistance syndrome. Besides the increased fre quency of diabetes, carriers showed a more atherogenic lipid profile, sugge sting a potential role of the IRS-1 gene in the pathogenesis of lipid abnor malities associated with CAD.