Segregation analysis of plasma lipoprotein(a) levels in pedigrees with molecularly defined familial hypercholesterolemia.

The role of genetic and environmental factors in determining the variability 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 mutant low density lipoprotein (LDL) receptor allele as confirmed by the identification of the specific mutations in addition to the haplotype analysis reported before. Four different mutant alleles were identified, each in a defined genetic group--Druze, Christian-Arabs, Ashkenazi, and Sepharidic 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 lipid levels and apo(a) isoforms. A mixture of two normal distributions fitted the adjusted Lp(a) levels better than did a single normal distribution. Segregation analysis indicated that a major effect of a non-transmitted environmental factor explained the mixture of distributions in addition to polygenic loci which influenced Lp(a) levels within each distribution. The major environmental factor and the polygenic loci accounted for 45% and 20% of the adjusted Lp(a) variation, respectively. Furthermore, sex, age, lipid levels, apo(a) isoform, the major environmental effect, and the unmeasured polygenes could account for 80% of the unadjusted variation of plasma Lp(a) in these families.