Genetics of the apolipoprotein E system in man.

The polymorphism of apolipoprotein E (Apo E) in man is controlled by two codominant alleles, Apo E(n) and Apo E(d), at the Apo E-N/D locus and by two alleles, the dominant, Apo E4(+), and the recessive, Apo E4(o), at the Apo E4 locus. Frequency distribution analysis of Apo E phenotypes demonstrated a highly significant association between both systems (P approximately 1%). The Apo E4-(+) variant was about twice as frequent in phenotype Apo E-N (30.1%) than in phenotype Apo E-ND (16.4%). The phenotypic combination Apo E-D/-E4(+) was not observed. The segregation of Apo E phenotypes in informative matings is consistent with a close linkage of both loci. The results may be explained by different models. On the basis of the present data, these models cannot be distinguished by formal genetic criteria. (1) Haplotypes Apo E(n)/E4(+), Apo E(n)/E4(o), and Apo E(d)/E4(o) determine the different phenotypes, and a linkage disequilibrium exists of Delta = .0147 between the E-N/D and E4 loci. (2) The fourth haplotype, Apo E(d)/E4(+), exists, but the gene E4(+) is not expressed in coupling with Apo E(d). The four-haplotype model seems more attractive in view of Apo E-N/D polymorphism's quantitative character and of biochemical results, which show that phenotypes Apo E-N and Apo E-D differ in the apparent molecular weight (M(r)) of the respective major Apo E polymorphic form. Hence, the Apo E-N/D locus may control structural genes involved in the posttranslational modification of Apo E. (3) Finally, there may exist only one Apo E structural gene locus but with mutations at two sites susceptible to posttranslational modification.