Correspondence

Risk of Myocardial Infarction and Polymorphisms in Candidate Genes

N Engl J Med 2003; 348:1176-1177March 20, 2003

Article

To the Editor:

Yamada et al. (Dec. 12 issue)1 state that the identification of genotypes of the 4G–668/5G polymorphism of the gene encoding plasminogen-activator inhibitor type 1 may be a reliable means of predicting the risk of myocardial infarction in women. We performed a matched case–control study of the polymorphism in 298 Italian women, half of whom had had a first myocardial infarction before the age of 45 years; the others were healthy members of the hospital staff. This population was chosen because there is usually little coronary atherosclerosis among premenopausal women, in whom it is therefore biologically plausible that myocardial infarction is related to a genetic predisposition to thrombosis. Analysis of the association of the 4G–668/5G polymorphism with the risk of myocardial infarction, which gave an odds ratio of 1.6 (95 percent confidence interval, 1.2 to 2.1; P<0.001) in the Japanese women studied by Yamada et al., gave a nonsignificant odds ratio of 1.0 (95 percent confidence interval, 0.7 to 1.5) in the Italian women. Our sample size, considering the allelic frequency of the polymorphism, had a power of approximately 80 percent to detect odds ratios greater than or equal to 1.5. The selection by Yamada et al. of an unusual control group, one with a strikingly high prevalence of traditional risk factors for myocardial infarction, and the peculiar epidemiology of cardiovascular disease in Japan may account for the difference. We concur with Peters and Boekholdt, who suggest in their accompanying editorial2 that at least in white men and women, there is still no genetic marker that can be clinically used to predict myocardial infarction.

Pier M. Mannucci, M.D.
Flora Peyvandi, M.D.
Diego Ardissino, M.D.
IRCCS Maggiore Hospital, 20122 Milan, Italy
pmmannucci@libero.it

2 References

1. 1

   Yamada Y, Izawa H, Ichihara S, et al. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N Engl J Med 2002;347:1916-1923
   Full Text | Web of Science | Medline

2. 2

   Peters RJG, Boekholdt SM. Gene polymorphisms and the risk of myocardial infarction -- an emerging relation. N Engl J Med 2002;347:1963-1965
   Full Text | Web of Science | Medline

Author/Editor Response

We thank Mannucci et al. for their comments. We examined the relation of the 4G–668/5G polymorphism of the plasminogen-activator inhibitor type 1 gene to myocardial infarction in 1752 women (936 controls and 816 patients with myocardial infarction) and detected a significant association (odds ratio, 1.5; 95 percent confidence interval, 1.2 to 1.8; P=0.0008 in a dominant genetic model). Mannucci et al. did not detect such an association in a population of 298 Italian women. The population they studied was much smaller than ours, and the background characteristics, including conventional risk factors, of the Italian women are not described.

Given that our controls were recruited from among persons who had visited participating hospitals, they had conventional risk factors, including hypertension, diabetes mellitus, hypercholesterolemia, and smoking, but they had no history of coronary artery disease. Susceptibility genes for myocardial infarction can be identified from differences in polymorphisms between persons with conventional risk factors but no history of myocardial infarction and those with both risk factors and a history of myocardial infarction. In addition, we examined the relation of the plasminogen-activator inhibitor type 1 polymorphism to myocardial infarction by multivariate logistic-regression analysis with adjustment for age, body-mass index, and the prevalence of smoking, hypertension, diabetes mellitus, hypercholesterolemia, and hyperuricemia. Furthermore, the distribution of plasminogen-activator inhibitor type 1 genotypes in our controls was in Hardy–Weinberg equilibrium. Our controls were thus adequate for the analysis performed. Although the association of the 4G–668/5G polymorphism of the plasminogen-activator inhibitor type 1 gene with myocardial infarction remains controversial,1-3 it cannot be ruled out by the results of Mannucci et al.

Yoshiji Yamada, M.D., Ph.D.
Gifu International Institute of Biotechnology, Mitake, Gifu 505-0116, Japan

Mitsuhiro Yokota, M.D., Ph.D.
Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
myokota@med.nagoya-u.ac.jp

3 References

1. 1

   Eriksson P, Kallin B, van 't Hooft FM, Bavenholm P, Hamsten A. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci U S A 1995;92:1851-1855
   CrossRef | Web of Science | Medline

2. 2

   Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Miletich JP. Arterial and venous thrombosis is not associated with the 4G/5G polymorphism in the promoter of the plasminogen activator inhibitor gene in a large cohort of US men. Circulation 1997;95:59-62
   Web of Science | Medline

3. 3

   Roest M, van der Schouw YT, Banga JD, et al. Plasminogen activator inhibitor 4G polymorphism is associated with decreased risk of cerebrovascular mortality in older women. Circulation 2000;101:67-70
   Web of Science | Medline