IMPACT OF APOLIPOPROTEIN-E POLYMORPHISM ON LIPOPROTEINS AND RISK OF MYOCARDIAL-INFARCTION - THE ECTIM STUDY

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 t his polymorphism with lipids, apolipoproteins, and lipoproteins with a particular regard to lipoprotein particles, as defined by their apoli poprotein content, as well as the risk of myocardial infarction in a m ulticenter population-based case-control study (ECTIM study). In the E CTIM study, 574 male patients aged 25 to 64 were examined 3 to 9 month s after myocardial infarction in four regions participating in the Wor ld Health Organization MONICA project: Belfast (Northern Ireland) and Lille, Strasbourg, and Toulouse (France). Control subjects (n = 722) w ere 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 poly morphism with biological measurements was studied in the control group s (n = 640) after men with coronary heart disease or those taking hypo lipidemic drugs were omitted, with the apoE3/3 phenotype as a referenc e after adjustment for concomitant factors. Individuals carrying the e psilon 2 allele had lower levels of plasma cholesterol, low-density li poprotein cholesterol (LDL-C), and apoB and higher levels of triglycer ides, very-low-density lipoprotein cholesterol (VLDL-C), apoC-III, apo E, lipoprotein (Lp) C-III: B, and Lp E:B. However, the effect of the e psilon 2 allele on triglyceride, VLDL-C, apoE, and Lp E:B parameters w as heterogeneous across the populations. The magnitude of these effect s was large and statistically significant in Lille and Strasbourg, whe reas only apoE was increased in Toulouse, and no effect of the epsilon 2 allele appeared in Belfast. The epsilon 4 allele was associated wit h increased triglyceride, VLDL-C, apoB, and Lp C-III:B levels and a de creased LpA-I level, but apoC-III, apoE, and Lp E:B levels were simila r to those with the apoE3/3 phenotype. The relative risk of myocardial infarction associated with apoE phenotypes compared with E3/3 was fou nd 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 all eles carried a relative risk of 0.73 (P=.05) and 1.33 (P=.02), respect ively, in a codominant logistic model, and no heterogeneity between ce nters was demonstrated. In conclusion, men carrying the epsilon 4 alle le present an atherogenic lipid and lipoprotein profile compared with E3/3 and are at higher risk of coronary heart disease in the populatio ns under study. Men carrying the epsilon 2 alIele have lower apoB leve ls 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 all ele on lipid metabolism. ApoE polymorphism, however, seems to explain a modest proportion, 12%, of myocardial infarction cases at the popula tion level.