INFLUENCE OF APOLIPOPROTEIN-E GENOTYPES ON PLASMA-LIPID AND LIPOPROTEIN CONCENTRATIONS - RESULTS FROM A SEGREGATION ANALYSIS IN PEDIGREES WITH MOLECULARLY DEFINED FAMILIAR HYPERCHOLESTEROLEMIA

Familal hypercholesterolemia (FH) is a monogenic disorder caused by mu tations in the low-density lipoprotein (LDL) receptor gene. Large vari ations in plasma lipids and lipoprotein levels have been observed in F H families. These may be caused by other enviornmental and genetic fac tors of which apolipoprotein E (ape E) is a candidate. The possible in fluence of apo E polymorphism on components of variation in plasma LDL -C, triglycerides, high-density lipoprotein cholesterol (HDL-C), and l ipoprotein(a) (Lp(a)) levels was investigated in 235 members of 14 fam ilies with FH. Sex- and age-adjusted mean LDL-C was influenced signifi cantly by the apo E genotype in non-FH subjects (P less than or equal to .01), and a similar trend was observed in FH cases. Mean plasma lev els of triglyceride, HDL-C, and Lp(a) were not significatnly different across the apo E genotypes in FH and in non-FH family members. Comple x segregation analysis was first applied to these sex- and age adjuste d data. In addition to the major gene involved in LDL-C levels (i.e., the LDL receptor gene), there was evidence for a nontransmitted enviro nmental major factor in addition to polygenic effect that explained th e mixture of distributions in TG and a major effect in addition to pol ygenic 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 ou siotype (class) specific, the results suggested that apo E genotypes h ave 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 lipoprote ins in FH. (C) 1996 Wiley-Liss, Inc.