Genetic transmission of isoapolipoprotein E phenotypes in a large kindred: relationship to dysbetalipoproteinemia and hyperlipidemia.

The largest reported kindred of a proband with type III hyperlipoproteinemia was investigated by assessment of lipid and lipoprotein levels and very low density lipoprotein (VLDL) isoapolipoprotein E distributions in all accessible family members (56% of the 124 living blood relatives and 59% of the 37 spouses). The results confirm in this kindred a trimodal distribution of apoE3/E2 ratios, and segregation analysis of 16 informative matings classified according to E3/E2 ratio demonstrated classical Mendelian inheritance of the autosomal codominant type: the E3/E2 ratio is determined by two alleles, apoE3d and apoE3n, which produce three phenotypes apoE3-D, apoE3-ND, and apoE3-N, corresponding to the low, intermediate, and high modes, respectively. Vertical transmission of the apoE3-D phenotype occurred in two branches of the second generation. In both instances this represented pseudodominance; i.e., products of heterozygous (apoE3-ND) x homozygous (apoE3-D) matings. Hyperlipidemia (defined as a low density lipoprotein cholesterol and/or plasma triglyceride level exceeding the respective age-, sex-, and sex-steroid-specific 95th percentiles derived from Lipid Research Clinics population studies) was present in 15 blood relatives in multiple lipoprotein patterns, consistent with the presence of familial combined hyperlipidemia in this kindred. Eight of nine members with the apoE3-D phenotype had either type III hyperlipoproteinemia or, in the absence of hyperlipidemia, beta-VLDL and at least marginally cholesterol-rich VLDL (VLDL-cholesterol/plasma triglyceride greater than 0.25) (defined as dysbetalipoproteinemia). The ninth such member, the only child with this phenotype, was normal. beta-VLDL and marginally cholesterol-rich VLDL was seen in but one of six hyperlipidemic family members of phenotype apoE3-ND, in none of seven hyperlipidemic blood relatives of phenotype apoE3-N, in no normolipidemic family members of phenotype apoE3-ND or apoE3-N, and in no spouses (three of whom were hyperlipidemic and nine of phenotype apoE3-ND). Thus, among adult members of the O'D kindred the apo3-D phenotype was nearly specifically associated with dysbetalipoproteinemia or, when hyperlipidemia was present, type III hyperlipoproteinemia.