POLYMORPHISMS OF THE APOLIPOPROTEIN-E GENE AND SEVERITY OF CORONARY-ARTERY DISEASE DEFINED BY ANGIOGRAPHY

In a recent study, we could account for only about 50% of the variance in angiographically determined severity of coronary artery disease (C AD) with use of lipid and clinical variables as predictors. To explore the possible contribution of the apolipoprotein (ape) E polymorphisms to the severity of CAD (rather than to its occurrence), we studied 42 4 white patients aged 65 years or less consecutively referred for coro nary angiography. Among the 304 male and 120 female patients, there we re 110 with no significant CAD and 118 with one, 96 with two, and 100 with three significantly diseased major coronary arteries (> 50% lumin al obstruction). The allele frequencies were 0.068 for E2, 0.759 for E 3, and 0.172 for E4. The E2 frequency was slightly lower and E4 higher than the frequencies reported for healthy white populations (E2: 0.07 2 to 0.130; E4: 0.136 to 0.160). There was a clear association between the apo E genotype and the number of significantly diseased vessels ( regression coefficient = .12, P = .008). The frequency of the E4 allel e increased linearly with the increase in CAD severity in both sexes ( for none, one, two, and three significantly diseased vessels; female p atients: 0.136, 0.161, 0.200, and 0.324; male patients: 0.136, 0.167, 0.132, and 0.229, respectively, P < .01). The frequencies of the E2 al lele, on the other hand, decreased with increasing severity (for none, one, two, and three significantly diseased vessels; female patients: correlation was mediated through apo E-related changes in circulating levels of apo B and apo B-containing lipoproteins, after controlling f or these lipid variables, there was an independent association between apo E genotype and CAD severity (P < .05). Among the 311 CAD patients who were not receiving lipid-lowering drugs at the time of testing, t he E2 allele was significantly associated with low apo B levels (- 21% for male patients, P < .01, and - 9% for female patients, P < .05 com pared with E3E3 genotypes, whereas the E4 allele was associated with h igh apo B levels (+ 12.4% for male patients, P < .05, and + 19.8% for female patients, P < .01). We conclude that among patients with corona ry disease, the apo E4 allele is associated with more severe and the E 2 allele with less severe disease. While the apo E genotype had an imp ortant effect on the level of circulating apo B-containing lipoprotein levels, these associations with severity were mediated not only by ch anges in circulating apo B but also by mechanisms unrelated to circula ting lipids in this population of CAD patients.