Human apolipoprotein (apo) E, a polymorphic protein with three common alleles, epsilon 2, epsilon 3, and epsilon 4, plays an important role in lipoprotein metabolism. This article describes the association of this polymorphism with lipids, apolipoproteins, and lipoproteins with a particular regard to lipoprotein particles, as defined by their apolipoprotein content, as well as the risk of myocardial infarction in a multicenter population-based case-control study (ECTIM study). In the ECTIM study, 574 male patients aged 25 to 64 were examined 3 to 9 months after myocardial infarction in four regions participating in the World Health Organization MONICA project: Belfast (Northern Ireland) and Lille, Strasbourg, and Toulouse (France). Control subjects (n = 722) were randomly selected from the regional populations. The distribution of apoE phenotypes was significantly different across the four control samples (P = .04), with a higher frequency of the epsilon 4 allele in Belfast (14.3%) than in Toulouse (8.2%). The association of apoE polymorphism with biological measurements was studied in the control groups (n = 640) after men with coronary heart disease or those taking hypolipidemic drugs were omitted, with the apoE3/3 phenotype as a reference after adjustment for concomitant factors. Individuals carrying the epsilon 2 allele had lower levels of plasma cholesterol, low-density lipoprotein cholesterol (LDL-C), and apoB and higher levels of triglycerides, very-low-density lipoprotein cholesterol (VLDL-C), apoC-III, apoE, lipoprotein (Lp) C-III: B, and Lp E:B. However, the effect of the epsilon 2 allele on triglyceride, VLDL-C, apoE, and Lp E:B parameters was heterogeneous across the populations. The magnitude of these effects was large and statistically significant in Lille and Strasbourg, whereas only apoE was increased in Toulouse, and no effect of the epsilon 2 allele appeared in Belfast. The epsilon 4 allele was associated with increased triglyceride, VLDL-C, apoB, and Lp C-III:B levels and a decreased LpA-I level, but apoC-III, apoE, and Lp E:B levels were similar to those with the apoE3/3 phenotype. The relative risk of myocardial infarction associated with apoE phenotypes compared with E3/3 was found to increase in the following order: E2/2<E3/2<E3/3 (relative risk=1) <E4/3=E4/2<E4/4 (P<.05). The presence of epsilon 2 and epsilon 4 alleles carried a relative risk of 0.73 (P=.05) and 1.33 (P=.02), respectively, in a codominant logistic model, and no heterogeneity between centers was demonstrated. In conclusion, men carrying the epsilon 4 allele present an atherogenic lipid and lipoprotein profile compared with E3/3 and are at higher risk of coronary heart disease in the populations under study. Men carrying the epsilon 2 alIele have lower apoB levels and appear to be at lower risk despite higher triglyceride and Lp E:B levels, at least in some regions. This suggests that other genes or environmental factors play an interactive role with the epsilon 2 allele on lipid metabolism. ApoE polymorphism, however, seems to explain a modest proportion, 12%, of myocardial infarction cases at the population level.
