No abstract

We explored the associations between G-->A mutations of factor V and factor VII genes and the Hae III polymorphism of the fibrinogen gene and the severity of coronary artery disease (CAD), as assessed angiographically in 545 white Australian patients (388 male and 157 female) aged < or = 65 years. We also assessed the relations with other potentially atherogenic variables. Elevated fibrinogen levels were associated with more severe CAD (P < .05), but none of the factor V, factor VII, and fibrinogen DNA variants were predictive of CAD severity, as assessed by the number of significantly diseased vessels (> 50% luminal obstruction). The rare allele frequencies of factor V (A allele), factor VII (M2 allele), and fibrinogen (H2 allele) were .025, .114, and .201 for men and .022, .077, and .169 for women, respectively, and were not different from those in healthy whites. In the patient population, there was a strong, positive association between lifetime smoking dose (in pack-years) and circulating fibrinogen levels (r = .184, P = .001). This association was stronger than that between current smoking habit and fibrinogen and is consistent with a dosage effect. However, there was no significant contribution of fibrinogen genotype to fibrinogen levels in this patient population. We conclude that elevated fibrinogen levels are associated not only with the occurrence of CAD but also with more severe CAD and that measurement of DNA variants of the factor V, factor VII, and fibrinogen genes that we assessed may not provide information in predicting CAD severity in addition to that obtained by measuring circulating levels of the relevant clotting factors. There is, moreover, a positive dosage effect (in pack-years) of smoking on circulating fibrinogen levels.

Angiotensin-converting enzyme is a key component of the renin-angiotensin system that plays an important role in cardiovascular regulation. An association between the angiotensin-converting enzyme insertion/deletion (I/D) polymorphism and increased coronary risk has been found in some studies but not in others. To explore this further in an Australian white population, we compared the ACE genotype distribution in 550 patients aged 37 to 65 years with coronary artery disease documented by angiography with the genotype distribution in 404 healthy school children aged 6 to 13 years. We also explored associations in the patients between the angiotensin-converting enzyme I/D polymorphism and a history of myocardial infarction and coronary artery disease severity assessed by the number of major coronary arteries with more than 50% luminal obstructions and by the Green Lane coronary score. The frequencies of the angiotensin-converting enzyme genotype in the coronary artery disease patients were 0.236 for I/I, 0.395 for I/D, and 0.369 for D/D genotypes. This distribution with an excess of the D/D genotype was significantly different (chi 2 = 23.69, P < .0001) from that in the school children, in whom the genotype distribution was in Hardy-Weinberg equilibrium (I/I, 0.21; I/D, 0.54; D/D, 0.25). There was also a significant excess of D/D genotype among patients with a history of myocardial infarction (chi 2 = 9.42, P = .009), and there was the same D/D excess in the subgroup of children (n = 60) with two or more grandparents who had had coronary artery disease. We found no associations between the angiotensin-converting enzyme polymorphism and the number of significantly stenosed coronary arteries (chi 2 = 2.069, P = .91). We conclude that the D/D genotype is a significant predictor for coronary artery disease events in the Australian white population but is not a marker for angiographically assessed coronary artery disease severity. The angiotensin-converting enzyme genotype-associated increased risk for coronary events may be mediated more by angiotensin II-induced coronary vasoconstriction than by an increase in injury-related smooth muscle cell proliferation in the coronary vasculature.