Influence of genetic variability in the nondeletion LDL-receptor allele on phenotypic variation in French-Canadian familial hypercholesterolemia heterozygotes sharing a 'null' LDL-receptor gene defect.

We investigated the associations between low density lipoprotein (LDL)-receptor gene haplotypes and lipid and lipoprotein levels in French-Canadian individuals with familial hypercholesterolemia (FH). The 112 unrelated patients studied shared the same > 10 Kb deletion in the 5' region of the LDL-receptor gene, leading to a null allele. Support for the hypothesis that the deletion is carried on only one LDL-receptor restriction fragment length polymorphism (RFLP) haplotype in this sample has previously been demonstrated [1]. We studied associations of genetic variability in DNA polymorphisms of the nondeletion LDL-receptor allele with variation in plasma lipid levels in these patients heterozygous for the deletion. All analyses were done separately in males and females. The traits were adjusted for variation in the concomitants age, height and weight, and for variation in apolipoprotein (apo) E phenotype, and then the association between variability in haplotypes defined by two RFLP loci and variation in trait levels were tested. The results indicated that in this sample of French-Canadian > 10 Kb deletion FH heterozygotes, variability at the LDL-receptor gene contributes to quantitative variation in measures of lipid metabolism and that the effects are different in males and females. The results indicated that variability at the LDL-receptor gene defined by two RFLP loci contributes to quantitative variation in high density lipoprotein (HDL)-cholesterol and LDL-cholesterol concentrations in French-Canadian FH women heterozygous for the > 10 Kb deletion and not in men.