ROLE OF THE APOLIPOPROTEIN-E POLYMORPHISM IN DETERMINING NORMAL PLASMA-LIPID AND LIPOPROTEIN VARIATION

Abstract

The structural gene locus for apolipoprotein E (apo E) is polymorphic. Three common alleles (.epsilon.2, .epsilon.3, .epsilon.4) code for 3 major isoforms in plasma and determine 6 apo E phenotypes that may be identified by isoelectric focusing on polyacrylamide. To establish what fraction of the inherited variation in a normal plasma lipid and lipoprotein profile is attributable to the segregation of the common alleles at the apo E gene locus, the average apo E allelic effects were estimated on plasma cholesterol (C), triglycerides, very low-density lipoprotein (VLDL)-C, VLDL-apo B, low-density lipoprotein (LDL)-C, LDL-apo B and high-density lipoprotein (HDL)-C in a representative sample of normolipidemic individuals from Ottawa, Canada. Data from published studies were also analyzed by the same statistical procedures. As much as 16% of the genetic variance (8.3% of the total variance) for LDL-C could be accounted for by the apo E gene locus. After correction for differences in age, sex, height and weight, the .epsilon.2 allele lowered and the .epsilon.4 allele raised total cholesterol, LDL-C and LDL-apo B. No other gene was identified that contributes as much to normal cholesterol variability. Analysis of these data and those of others also indicates that apo E locus imparts a differential susceptibility to a variety of factors that promote hyperlipidemia. The hypothesis is proposed that the .epsilon.2 allele protects against coronary heart disease (CHD) and, hence, gives a reproductive advantage that is balanced by a predisposition to CHD when the .epsilon.2 is combined with a 2nd, independent causative factor to give a reproductive disadvantage. A similar mechanism is proposed for the maintenance of the .epsilon.4 in the population.