© 2002 American Heart Association, Inc.
Letters to the Editor |
IRS-1 Gly971Arg Variant Is Not a New Risk Factor for Coronary Artery Disease in the Taiwanese Population
Cardiology Section, Department of Internal Medicine,, National Taiwan University Hospital,, Taipei, Taiwan
To the Editor:
We read with interest the recent article by Baroni et al1 who reported that the frequency of a glycine to arginine variant at codon 971 of the insulin receptor substrate-1 (IRS-1) gene was 2.5-fold higher in patients with angiographic coronary artery disease (CAD) than in normal controls. Furthermore, the risk of CAD increased to 3-fold even after adjusting for other classical CAD risk factors. These results imply that the IRS-1 variant may be a new genetic risk factor for CAD, which is independent of diabetes. In this respect, Delafontaine2 also expressed his excellent comments in a subsequent editorial. However, genetic risk factors for a complex trait disease may be different in different ethnic groups, and these findings will have to be confirmed by other studies. So far, there has been no second study exploring this issue.
Accordingly, we conducted a case-control study to confirm the association of the IRS-1 variant and angiographic CAD in the Taiwanese population. There were 300 consecutive subjects (201 men and 99 women, mean age 59 [20 to 83] years) who had undergone cardiac catheterization at our institution. Cases (n=195) were patients with at least one angiographic coronary artery lesion of >50% stenosis. Controls (n=105) were those without demonstrable angiographic CAD. Among the study population, there were 51 patients with clinical features of insulin resistance metabolic syndrome, the diagnosis of which was based on the published criteria by the World Health Organization.3 The Gly971Arg polymorphism was detected by nested polymerase chain reaction and BstNI restriction enzyme digestion, as reported by Baroni et al.1 Surprisingly, no Gly971Arg mutation was detected in any of the study population.
Our results are consistent with those reported by Chuang et al4 in 1996, in which only 1 (1.1%) of 89 Taiwanese patients with non-insulin–dependent diabetes mellitus (NIDDM) and 1 (1.2%) of the control subjects had Gly971Arg variant of the IRS-1 gene. The frequency of this variant ranged from 4% to 7% in the Western populations and was two times higher in patients with NIDDM.5–6 The frequency was 
3.5% in the Japanese population.7–8 Therefore, the frequency of the IRS-1 Gly971Arg variant is variable, not only among the Western and Eastern populations, but also among the East Asian populations.
Although the studies in the Western populations showed a statistically significant association of the IRS-1 variant with NIDDM and CAD,5–6 the results of the population association study looking for a genetic marker for a complex trait disease should be interpreted cautiously. The positive association in the population level between a gene and disease might come from causes other than linkage, such as population stratification or admixture. A more sensitive test for the presence of linkage, such as the transmission/disequilibrium test,9 may be necessary to provide evidence of linkage, although it may be difficult to perform in CAD patients, most if not all of whom are >55 years old, because of the difficulties in recruiting parents who are still alive.
Therefore, the frequency of the Gly971Arg variant in the IRS-1 gene is not uniform, and this variant as a new genetic risk factor for CAD cannot be confirmed in a different ethnic population. However, with regards to the possibility that mutations other than the Gly971Arg variant in the IRS-1 gene might be involved, sequence analysis in our population should be performed to exclude the IRS-1 gene as a risk factor for CAD.
This work was supported by a grant from the National Taiwan University Hospital (89515).
References
1.
Baroni MG, D’Andrea MP, Montali A, Pannitteri G, Barilla F, Campagna F, Mazzei E, Lovari S, Seccareccia F, Campa PP, Ricci G, Pozzilli P, Urbinati G, Arca M. A common mutation of the insulin receptor substrate-1 gene is risk factor for coronary artery disease. Arterioscler Thromb Vasc Biol. 1999; 19: 2975–2980.
2.
Delafontaine P. IRS-1 variant: a new risk factor for coronary artery disease? Arterioscler Thromb Vasc Biol. 2000; 20: 283–284.
3. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications, Part 1: diagnosis and classification of diabetes mellitus: provisional report of a WHO consultation. Diabetic Med. 1998; 15: 539–553.[CrossRef][Medline] [Order article via Infotrieve]
4. Chuang LM, Lai CS, Yeh JI, Wu HP, Tai TY, Lin BJ. No association between the Gly971Arg variant of the insulin receptor substrate-1 gene and NIDDM in the Taiwanese population. Diabetes Care. 1996; 19: 446–449.[Abstract]
5. Hitman GA, Hawrami K, McCarthy MI, Viswanathan M, Snehalatha C, Ramachandran A, Tuomilehto J, Tuomilehto-Wolf E, Nissinen A, Pedersen O. Insulin receptor substrate-1 gene mutations in NIDDM: implications for the study of polygenic disease. Diabetologia. 1995; 38: 481–486.[Medline] [Order article via Infotrieve]
6. Zhang Y, Wat N, Stratton IM, Warren-Perry MG, Orho M, Groop L, Turner RC. UKPDS19: heterogeneity in NIDDM: separate contribution of IRS-1 and beta3-adrenergic-receptor mutations to insulin resistance and obesity respectively with no evidence for glycogen synthase gene mutations. Diabetologia. 1996; 39: 1505–1511.[CrossRef][Medline] [Order article via Infotrieve]
7. Mori H, Hashiramoto M, Kishimoto M, Kasuga M. Amino acid polymorphisms of the insulin receptor substrate-1 in Japanese noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1995; 80: 2822–2826.[Abstract]
8. Ura S, Araki E, Kishikawa H, Shirotani T, Todaka M, Isami S, Shimoda S, Yoshimura R, Matsuda K, Motoyoshi S, Miyamura N, Kahn CR, Shichiri M. Molecular scanning of the insulin receptor substrate-1 (IRS-1) gene in Japanese with NIDDM: identification of five novel polymorphisms. Diabetologia. 1996; 39: 600–608.[Medline] [Order article via Infotrieve]
9. Spielman RS, McGinnis RE, Ewens WJ. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet. 1993; 52: 506–516.[Medline] [Order article via Infotrieve]
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