Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype

Seventy-one mutations of the low density lipoprotein (LDL) receptor gene we re identified in 282 unrelated Italian familial hypercholesterolemia (FH) h eterozygotes. By extending genotype analysis to families of the index cases , we identified 12 mutation clusters and localized them in specific areas o f Italy. To evaluate the impact of these mutations on the clinical expressi on of FH, the clusters were separated into 2 groups: receptor-defective and receptor-negative, according to the LDL receptor defect caused by each mut ation. These 2 groups were comparable in terms of the patients' age, sex di stribution, body mass index, arterial hypertension, and smoking status. In receptor-negative subjects, LDL cholesterol was higher (+18%) and high dens ity lipoprotein cholesterol lower (-5%) than the values found in receptor-d efective subjects. The prevalence of tendon xanthomas and coronary artery d isease (CAD) was 2-fold higher in receptor-negative subjects. In patients > 30 years of age in both groups, the presence of CAD was related to age, art erial hypertension, previous smoking, and LDL cholesterol level. Independen t contributors to CAD in the receptor-defective subjects were male sex, art erial hypertension, and LDL cholesterol level; in the receptor-negative sub jects, the first 2 variables were strong predictors of CAD, whereas the LDL cholesterol level had a lower impact than in receptor-defective subjects. Overall, in receptor-negative subjects, the risk of CAD was 2.6-fold that o f receptor-defective subjects. Wide interindividual variability in LDL chol esterol levels was found in each cluster. Apolipoprotein E genotype analysi s showed a lowering effect of the epsilon 2 allele and a raising effect of the epsilon 4 allele on the LDL cholesterol level in both groups; however, the apolipoprotein E genotype accounted for only 4% of the variation in LDL cholesterol. Haplotype analysis showed that all families of the major dust ers shared the same intragenic haplotype cosegregating with the mutation, t hus suggesting the presence of common ancestors.