© 2000 American Heart Association, Inc.
Editorials |
IRS-1 Variant
A New Risk Factor for Coronary Artery Disease?
1 Professor of Medicine and,
Chairman, Division of Cardiology,
University Hospital,
Geneva, Switzerland
From the Division of Cardiology, University Hospital, Geneva,
Switzerland.
Correspondence to P. Delafontaine, MD, FACC, Professor of Medicine, Chairman, Division of Cardiology, University Hospital, Rue Micheli-du-Crest 24, 1211 Geneva 14, Switzerland. E-mail Patrice.Delafontaine{at}hcuge.ch
The genetic predisposition to develop coronary artery disease, while well established,1 2 3 is incompletely understood. Much attention has focused on lipoprotein abnormalities that may contribute to this genetic predisposition.3 4 Another recent candidate has been a polymorphism of the angiotensin-converting enzyme gene, specifically the DD genotype, that has been associated with higher circulating levels of angiotensin-converting enzyme activity and has been found in some studies, but not all, to be a risk factor for myocardial infarction.5 6
In a recent issue of Arteriosclerosis, Thrombosis, and Vascular Biology (Arterioscler Thromb Vasc Biol. 1999;19:2975–2980), Baroni and coworkers7 have studied the frequency of a mutation of the insulin receptor substrate-1 (IRS-1) gene in 318 patients with angiographic evidence of a coronary artery stenosis of >50%. The frequency of this mutation was 2.5-fold higher in these patients compared with 208 control individuals. When adjusted for other risk factors, the relative risk of angiographic coronary disease attributable to the IRS-1 polymorphism was 3-fold, and it increased to 7-fold and 23-fold, respectively, in obese patients and in patients with the insulin resistance syndrome. The latter has been defined as the presence of 2 or more characteristics that include hypertension, obesity, plasma triglycerides >2.26 mmol/L (200 mg/dL), and high fasting insulin levels. Thus, this study provides a new candidate gene potentially contributing to the genetic predisposition to develop coronary artery disease, a polygenic disorder.
The mechanisms whereby the glycine-to-arginine substitution at codon 972 of the IRS-1 gene could lead to an increased risk for coronary disease are not clear. IRS-1 functions as a key proximal signaling molecule for both the insulin and the insulin-like growth factor-1 receptor signal transduction pathways. When phosphorylated, IRS-1 binds with high affinity to proteins with src homology-2 domains, including phosphatidylinositol 3'-kinase.8 In an analysis of several studies, the IRS-1 codon 972 variant has been reported to have an overall frequency of 10.7% in patients with non–insulin dependent diabetes mellitus (NIDDM) compared with 5.8% in normals, suggesting that this mutation acts as a susceptibility locus predisposing to insulin resistance.9 Almind et al10 originally reported that the IRS-1 codon 972 variant did not confer insulin resistance but that patients with this defect had lower levels of fasting insulin and C-peptide. Laakso et al11 subsequently confirmed the lack of a clear association between the IRS-1 variant and insulin resistance, as measured by insulin secretion capacity and insulin action. However, in a more recent work by Clausen and coworkers,12 a significant interaction between obesity and the IRS-1 variant was demonstrated. Thus, in carriers of the polymorphism there was clearly decreased insulin sensitivity, as well as a clustering of metabolic cardiovascular risk factors including raised fasting glucose, serum triglycerides, plasma tissue plasminogen activator, and its inhibitor. Also, in a recent analysis, NIDDM patients with insulin resistance (with or without hypertriglyceridemia) have been reported to have a higher prevalence of the IRS-1 polymorphism.13
Transfection studies have shown that the IRS-1 codon 972 mutation produces defective insulin receptor signaling, including decreased IRS-1–associated phosphatidylinositol 3'-kinase activity and decreased insulin-stimulated DNA synthesis.14 Thus, these studies suggest that the IRS-1 mutation may be associated with impaired insulin signaling and contribute to the insulin resistance syndrome, which includes obesity, NIDDM, hypertension, and hypertriglyceridemia. There is significant evidence that diabetes and insulin resistance increase the risk for coronary artery disease.15 16 17 Thus, a potential mechanism whereby the IRS-1 mutation could contribute to the risk for coronary disease is by predisposing individuals to diabetes and other metabolic risk factors. Although the IRS-1 gene variant in the report of Baroni et al7 was associated with a higher frequency of diabetes and hypertriglyceridemia, the increased risk of coronary disease was independent of diabetes. It is not clear whether the multivariate analysis included triglyceride levels and thus whether the increased risk of coronary disease was independent of these levels. This is important, because IRS-1 mutation carriers had 60% higher triglyceride levels. In this respect, it is interesting to note that in the IRS-1–deficient mouse, blood pressure and plasma triglyceride levels are significantly higher.18 Perhaps the most intriguing finding in the report of Baroni et al7 is that the association of obesity with the IRS-1 mutation greatly potentiates the risk of coronary disease conferred by the polymorphism alone. These findings will have to be confirmed by other studies. Particularly, the association of the IRS-1 mutation and clinical coronary events needs to be demonstrated; risk factors predisposing to angiographic evidence of coronary disease may differ from those predicting clinical events.19 However, this report provides a new and potentially important link in the net of genetic and environmental factors that interact to produce clinical coronary artery disease.
Received June 16, 1999; accepted July 9, 1999.
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