Apolipoprotein (apo) E polymorphism was among the first-reported genetic polymorphisms that explained part of the normal variation in plasma cholesterol concentrations in hnmans. The aim of this study was to assess the influence of allelic variation at the apo E gene locus on the plasma lipoprotein profile in hyperlipidemia. The lipoprotein levels of hyperlipidemic subjects of the major apo E phenotypes (E3/2, E3/3, and E4/3) were compared. One hundred eighty-two subjects with endogenous hypertriglyceridemia and 98 subjects with familial hypercholesterolemia due to a 10-kb deletion in their low density lipoprotein (LDL) receptor genes were compared with 424 normolipidemic controls from the same environmental background. LDL concentrations were lower in the E3/2 subset than in the E3/3 or E4/3 subset in the control, hypertriglyceridemic, and familial hypercholesterolemic groups. In absolute values, the magnitude of the effect was greatest in the familial hypercholesterolemic group. However, the direction and percentage change were identical in the presence or absence of the LDL receptor defect, indicating that the apo E phenotype effect is independent of LDL receptor status. Triglyceride and very low density lipoprotein (VLDL) cholesterol concentrations were higher in E3/2 than in E3/3 or E4/3 hypertriglyceridemic subjects, but this difference was not found in the familial hypercholesterolemic or control group. Thus, there seems to be a specific interaction between apo E isoforms and VLDL metabolism in hypertriglyceridemia; allelic variation at the apo E gene locus seems to be associated with specific alterations in the plasma lipoprotein profile of subjects with well-defined types of hyperlipidemia. (Arteriosclerosis and Thrombosis 1991;ll:272-278) P lasma concentrations of lipoproteins, as well as their metabolic fate, are regulated by apolipoproteins (apos) on their surfaces. Among these apos, apo E is a polymorphic protein that determines the catabolism of chylomicron remnants. Three major alleles (e2, e3, and e4) at a single gene locus determine the phenotypic expression of apo E.1 The E2 isoform differs from the most common E3 by a single amino acid substitution in position 158 (Arg-*Cys) of the 299-amino acid chain and displays low-affinity binding to the low density lipoprotein (LDL) receptor in vitro.2 E4 differs from E3 by a single amino acid substitution in position 112 (Cys->Arg) and displays normal affinity for the LDL (B/E) receptor. 3 In vivo, there is evidence that apo E2 carried on triglyceride-rich particles is cleared from plasma more slowly and apo E4 more rapidly than is apo E3.3 -
4The genetic polymorphism of apo E contributes to the normal variation of plasma lipid and lipoprotein concentrations in population studies.5 This has been demonstrated in normolipidemic individuals and in various selected populations.6 -17 Total and LDL cholesterol concentrations are consistently lower in apo E2-bearing subjects, 6 -17 whereas apo E4 is associated with increased LDL cholesterol in a variety of pop...