Lack of association of the Gly972Arg mutation of the insulin receptor substrate‐1 gene with coronary artery disease in the Austrian population

Dear Sir, The insulin resistance syndrome is considered as a potent risk factor for the development of atherosclerotic vascular disease [1, 2]. A base change at codon 972 of the insulin receptor substrate-1 (IRS-1) gene resulting in an arginine for glycine substitution has been found to be associated with the insulin resistance syndrome and predisposition to noninsulin dependent diabetes mellitus (NIDDM) [3, 4]. Baroni and coworkers [5] reported that the G972R mutation in the IRS-1 gene was significantly associated with increased risk of coronary artery disease (CAD), particularly in subgroups of individuals with obesity and insulin resistance syndrome. Overall, heterozygous subjects showed a CAD risk almost three times higher than wild-type carriers. These results suggested that the IRS-1 gene variant might be a new genetic risk factor for CAD independent of diabetes or hyperlipidemia. However, there is evidence that the frequency of the G972R mutation in the IRS-1 gene is variable in different ethnic and regional populations [6, 7], complicating the interpretation of the influence of this polymorphism on CAD risk [8, 9]. We performed a case–control study in order to test the association of this common mutation with the presence of CAD in the Austrian population. The study group comprised a total of 436 consecutive unrelated subjects who underwent coronary angiography at our hospital. The patient group consisted of 215 subjects with CAD (163 male, 52 female patients; mean age 58 ± 8 years). Diagnostic criteria for recruitment to the patient cohort were one or more stenoses >50% in at least one major coronary artery. The control group consisted of 221 subjects (110 male, 111 female patients; mean age 60 ± 8 years) with chest pain suggestive of angina. To qualify as control, subjects had to be without visible signs of atherosclerotic lesions in the standard coronary angiogram. After informed consent genotypes of IRS-1 polymorphism were determined in all subjects by nested polymerase chain reaction and BstN1 restriction enzyme digestion, as described previously [5]. In the total study cohort 11.2% (49 of 436) were found to be heterozygous for the G972R mutation in the IRS-1 gene. Most interestingly, the frequency of G972R mutation carriers was similar in the patient and control group [11.2% (24 of 215) vs. 11.3% (25 of 221); P = NS). No association was found between this mutation and the CAD status, neither for male (P = 0.46) nor for female (P = 0.40) subjects. Moreover, no direct interaction was observed between IRS-1 type and risk of CAD in obese patients [body mass index (BMI) > median]. The group with CAD contained 20.5% (44) patients with diabetes, whereas only 8.6% (19) diabetics were found among controls (P < 0.001). We found no significant difference in genotype frequency between carriers and noncarriers with respect to clinical characteristics (BMI, hypertension) except for a higher prevalence in the small subgroup of male subjects with diabetes [31% (nine of 29) vs. 12.3% (30 of 244); P = 0.005, respectively]. As far as biochemical characteristics are concerned, male mutation carriers showed significantly higher values of fasting insulin, female mutation carriers higher levels of triglycerides and low density lipoprotein cholesterol. Other biochemical parameters did not reach statistical significance when compared with the presence of the G972R mutation. Insulin resistance syndrome and type 2 diabetes are nowadays thought to result from polygenic interactions of several inherited gene mutations. The IRS-1 gene may act as susceptibility gene predisposing to manifestation of NIDDM [10, 11]. A group of investigators proposed to include angiographically documented CAD in the disease cluster comprising the insulin resistance syndrome [2]. However, other investigators suggested that the IRS-1 gene is not implicated in the pathogenesis of NIDDM or atherosclerotic vascular disease [9, 12, 13]. Most likely, discrepancies in association studies arise from unsuspected population stratification, even in ethnically homogenous populations as presented here. In contrast to the study by Baroni et al. [5], subjects with angina-like chest pain, abnormal stress test and normal epicardial coronary arteries were included in our control group. These characteristics resemble cardiac syndrome X, which occurs more frequently in patients with coronary artery disease risk factors, such as high fasting insulin and lipoprotein levels [14]. It is conceivable, that the prevalence of the IRS-1 variant in those patients is substantial different from that in healthy controls. Applying exact permutational methods, the number of subjects needed to achieve a conventional level of significance, assuming a 5% difference in the prevalence of the polymorphism, has been estimated to be 380 subjects in each group [7]. Although our study lacks the power to determine an association between a gene and a complex disease in the population level, the data might be useful for a future meta-analysis. With regard to the contribution of this genetic polymorphism to CAD risk, we believe that the interplay between several environmental and genetic factors needs to be strongly considered. No conflict of interest was declared.