Influence of apolipoprotein E genotypes on plasma lipid and lipoprotein concentrations: results from a segregation analysis in pedigrees with molecularly defined familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is a monogenic disorder caused by mutations in the low-density lipoprotein (LDL) receptor gene. Large variations in plasma lipids and lipoprotein levels have been observed in FH families. These may be caused by other environmental and genetic factors of which apolipoprotein E (apo E) is a candidate. The possible influence of apo E polymorphism on components of variation in plasma LDL-C, triglycerides, high-density lipoprotein cholesterol (HDL-C), and lipoprotein(a) (Lp(a)) levels was investigated in 235 members of 14 families with FH. Sex-and age-adjusted mean LDL-C was influenced significantly by the apo E genotype in non-FH subjects (P <or= .01), and a similar trend was observed in FH cases. Mean plasma levels of triglyceride, HDL-C, and Lp(a) were not significantly different across the apo E genotypes in FH and in non-FH family members. Complex segregation analysis was first applied to these sex- and age-adjusted data. In addition to the major gene involved in LDL-C levels (i.e., the LDL receptor gene), there was evidence for a non-transmitted environmental major factor in addition to polygenic effect that explained the mixture of distributions in TG and a major effect in addition to polygenic loci which influenced Lp(a) levels. There was no evidence for a single major factor controlling HDL-C levels in these pedigrees. When the segregation models allowed apo E regression coefficients to be ousiotype (class) specific, the results suggested that apo E genotypes have a significant effect on LDL-C, TG, and Lp(a) levels. In conclusion, the analysis presented here supports the concept that the apo E gene has an important role in the regulation of plasma lipid and lipoproteins in FH.