Polymorphisms of the Apolipoprotein E Gene and Severity of Coronary Artery Disease Defined by Angiography

Abstract

Abstract In a recent study, we could account for only about 50% of the variance in angiographically determined severity of coronary artery disease (CAD) with use of lipid and clinical variables as predictors. To explore the possible contribution of the apolipoprotein (apo) E polymorphisms to the severity of CAD (rather than to its occurrence), we studied 424 white patients aged 65 years or less consecutively referred for coronary angiography. Among the 304 male and 120 female patients, there were 110 with no significant CAD and 118 with one, 96 with two, and 100 with three significantly diseased major coronary arteries (>50% luminal obstruction). The allele frequencies were 0.068 for E2, 0.759 for E3, and 0.172 for E4. The E2 frequency was slightly lower and E4 higher than the frequencies reported for healthy white populations (E2: 0.072 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 allele increased linearly with the increase in CAD severity in both sexes (for none, one, two, and three significantly diseased vessels; female patients: 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 allele, on the other hand, decreased with increasing severity (for none, one, two, and three significantly diseased vessels; female patients: 0.091, 0.018, 0.050, and 0.029; male patients: 0.073, 0.089, 0.072, and 0.054, respectively, P <.05). While much of the correlation was mediated through apo E–related changes in circulating levels of apo B and apo B–containing lipoproteins, after controlling for 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, the E2 allele was significantly associated with low apo B levels (−21% for male patients, P <.01, and −9% for female patients, P <.05) compared with E3E3 genotypes, whereas the E4 allele was associated with high apo B levels (+12.4% for male patients, P <.05, and +19.8% for female patients, P <.01). We conclude that among patients with coronary disease, the apo E4 allele is associated with more severe and the E2 allele with less severe disease. While the apo E genotype had an important effect on the level of circulating apo B–containing lipoprotein levels, these associations with severity were mediated not only by changes in circulating apo B but also by mechanisms unrelated to circulating lipids in this population of CAD patients.