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BACKGROUND: Although both genetic and nongenetic factors contribute to the pathogenesis of coronary artery disease, the identification of specific genetic lesions has lagged behind the identification of critical environmental risk factors. A reported association between myocardial infarction (MI) and the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene in European men suggests a critical role for this genomic region. However, the generality of this association remains to be determined. It also is not clear at what stage in disease progression the association with the ACE I/D polymorphism becomes important. METHODS AND RESULTS: We evaluated the ACE I/D polymorphism in patients who had undergone coronary angiography (402 men and 295 women) and in 203 representative control subjects. After polymerase chain reaction amplification, genotypes were determined by agarose gel sizing and by hybridization with allele-specific oligonucleotides. After patients were categorized by the degree of coronary artery stenosis and the occurrence of an MI, the distribution of ACE I/D genotypes was evaluated by log linear analysis. Patients were genetically representative of the regional population, and patients with > 60% stenosis of their coronary arteries had the same distribution of ACE I/D genotypes as did patients with < 10% stenosis. However, among patients with stenosis, the occurrence of an MI was significantly associated with the D allele in all patients (odds ratio OR, 1.59; P = .002) and in men alone (OR, 1.63; P = .006). The lack of significance in women (OR, 1.40; P = .263) is probably due to the fact that only 36 women in the present study had experienced an MI. Furthermore, the association between MI and the ACE I/D polymorphism was independent of blood pressure, smoking habits, and body mass index. CONCLUSIONS: Segregation of the ACE I/D polymorphism is a pervasive genetic risk factor for MI in whites but has no evident effect on the events leading to stenosis of the coronary arteries. This suggests that risk of MI is influenced by two independent processes--atherogenesis that leads to coronary stenosis followed by conversion to MI. The renin-angiotensin system appears to confer significant risk of infarction by influencing the conversion to MI but has no apparent effect on the development of atherostenosis.
Ludwig et al. (Sat,) studied this question.