Determinants of lipid level variability in French-Canadian children with familial hypercholesterolemia

The wide variability in the biochemical expression of familial hypercholest erolemia (FH) is only partly explained by mutational heterogeneity in the l ow density lipoprotein receptor (LDLR) gene. In the current study, we measu red this biochemical variability in a group of children heterozygous for th e > 15-kb LDLR gene deletion (n=67) and examined the contribution of apolip oprotein (apo) E and B allelic variations to this phenotypic variability. V ariances of total cholesterol (TC), LDL-C, and apoB concentrations and of t he ratio of TC to high density lipoprotein cholesterol (HDL-C) were increas ed in FH subjects compared with controls. However. after taking the means i nto account, the coefficients of variation showed that the variability of L DL-C and apoB concentrations was smaller for FH than for controls and that the variability of TC and of the ratio TC to HDL-C was similar between both groups. The epsilon2/3 genotype was associated with lower mean TC, LDL-C, and apoB concentrations in FH. The magnitude of this effect was smaller in controls than in FH. Indeed, the percentages of total variance of TC, LDL-C , and apoB attributable to the apoE locus were 19.9%, 18.1%, and 11.8%, res pectively, in FH cases and 5.9%, 7.4%, and 6.0%, respectively, in controls. We did not detect any effect of the apoB insertion/deletion polymorphism o n lipid traits in FH children. However, in controls, we observed a strong i nteraction between apoE and apoB genotypes on apoB concentrations and on TC to HDL-C ratios. Our study reemphasizes the important role of apoE in lipi d metabolism and illustrates that the effects of allelic variations on lipi d traits are context dependent.