A Common Mutation of the Insulin Receptor Substrate-1 Gene Is A Risk Factor for Coronary Artery Disease

Abstract

Abstract-Insulin resistance is associated with increased risk of atherosclerosis. Insulin receptor substrate-1 (IRS-1) plays a key role in tissue insulin sensitivity. A common mutation (G972R) of the IRS-1 gene has been shown to impair IRS-1 function, and it has been associated with reduced insulin sensitivity and lipid abnormalities. This led us to investigate the role of the G972R mutation in predisposing individuals to coronary artery disease (CAD). The DNA of 318 subjects with angiographically documented coronary atherosclerosis (Ͼ50% stenosis) and 208 population control subjects was analyzed for the presence of the G972R mutation. This mutation was detected by nested polymerase chain reaction and BstNI restriction enzyme digestion. The frequency of the G972R mutation was significantly higher among patients with CAD than controls (18.9% versus 6.8%, respectively; PϽ0.001). After controlling for other coronary risk factors, the relative risk of CAD associated with the G972R mutation was 2. 001).The IRS-1 gene variant was associated with a higher frequency of diabetes mellitus (14.9% among carriers versus 6.5% among noncarriers; PϽ0.01) and with a 60% increase of plasma total triglycerides (PϽ0.001). Also, plasma concentrations of total cholesterol and the ratio of total cholesterol to HDL cholesterol were significantly (PϽ0.001) higher among carriers than noncarriers, although to lesser a extent. These effects were independent 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 increased the risk of CAD in obese subjects and in patients with the cluster of abnormalities of insulin resistance syndrome. Besides the increased frequency of diabetes, carriers showed a more atherogenic lipid profile, suggesting a potential role of the IRS-1 gene in the pathogenesis of lipid abnormalities associated with CAD. (Arterioscler Thromb

Gly972Arg variant in the insulin receptor substrate-1 gene and association with Type 2 diabetes: a meta-analysis of 27 studies

“…This additional information was provided by nine authors on ten study populations [8,13,15,16,17,18,19,20,23].…”

“…Of the studies five were population-based studies [5,8,19,21] and 22 studies were hospital-based studies [2,3,4,6,9,10,11,12,13,14,15,16,17,18,20,22,23,26]. Seventeen studies included Caucasian subjects [2,3,4,5,8,11,12,14,15,18,19,20,22,23,26], eight studies included Asian subjects [6,8,9,10,13,16,17], and three studies black or South American subjects [15,21,23] (Fig.…”

“…Seventeen studies included Caucasian subjects [2,3,4,5,8,11,12,14,15,18,19,20,22,23,26], eight studies included Asian subjects [6,8,9,10,13,16,17], and three studies black or South American subjects [15,21,23] (Fig. 1).…”

“…1). Diagnostic tests to exclude diabetes in the control subjects were a single fasting blood glucose test in ten studies [2,3,8,14,18,19,20,21,22] and a glucose tolerance test in nine studies [5, 6, 8, 9, 10, 16, . In nine studies no diagnostic test has been used or reported [4,11,12,13,15,23,26].…”

“…Polymorphisms in the IRS-1 gene were identified for the first time in 1993 [2]. Since then, many case control studies have examined the association between the Gly972Arg variant and Type 2 diabetes [2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26]. Results, however, are not association between the Gly972Arg variant in the IRS-1 gene and the prevalence of Type 2 diabetes.…”