SEGREGATION ANALYSIS OF PLASMA LIPOPROTEIN(A) LEVELS IN PEDIGREES WITH MOLECULARLY DEFINED FAMILIAL HYPERCHOLESTEROLEMIA

The role of genetic and environmental factors in determining the varia bility in plasma lipoprotein(a) [Lp(a)] levels was investigated in 220 members of 14 families with familial hypercholesterolemia (FH) whose plasma Lp(a) levels were previously reported [Leitersdorf et al. (1991 ) J Lipid Res 32:1513-1519]. One hundred four subjects harbored a muta nt low density lipoprotein (LDL) receptor allele as confirmed by the i dentification of the specific mutations in addition to the haplotype a nalysis reported before. Four different mutant alleles were identified , each in a defined genetic group-Druze, Christian-Arabs, Ashkenazi, a nd Sephardic Jews. Sex- and age-adjusted mean plasma Lp(a) levels were significantly higher in FH family members (34.0 mg/dl) than in non-FH family members (21.1 mg/dl). Lp(a) levels were further adjusted for l ipid levels and apo(a) isoforms. A mixture of two normal distributions fitted the adjusted Lp(a) levels better than did a single normal dist ribution. Segregation analysis indicated that a major effect of a non- transmitted environmental factor explained the mixture of distribution s in addition to polygenic loci which influenced Lp(a) levels within e ach distribution. The major environmental factor and the polygenic loc i accounted for 45% and 20% of the adjusted Lp(a) variation, respectiv ely. Furthermore, sex, age, lipid levels, apo(a) isoform, the major en vironmental effect, and the unmeasured polygenes could account for 80% of the unadjusted variation of plasma Lp(a) in these families. (C) 19 95 Wiley-Liss, Inc.