© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Clinical Expression of Familial Hypercholesterolemia in Clusters of Mutations of the LDL Receptor Gene That Cause a Receptor-Defective or Receptor-Negative Phenotype
From the Department of Internal Medicine (S.B., L.P., M.R., S.L.), University of Genoa; the National Institute of Health (A.C., I.B.), Rome; the Institute of Internal Medicine (M.A.), University of Palermo, Palermo; the Department of Internal Medicine (C.C., C.M.), University of Rome "Tor Vergata," Rome; the Department of Medical Sciences (S.M.), University of Padua, Padua; the Institute of Clinical Biochemistry (G.P.), University of Sassari, Sassari; the Department of Clinical and Experimental Medicine (A.P.), University of Naples "Federico II," Naples; the Institute of Medical Therapy (C.S.), University of Rome, Rome; the Department of Biomedical Sciences (M.G., S.C.), University of Modena and Reggio Emilia, Modena; and the Department of Pediatrics (I.R.), University of Turin, Turin, Italy.
Correspondence to Sebastiano Calandra, Department of Biomedical Sciences, University of Modena and Reggio Emilia, Via Campi, 287, 41100 Modena,-Italy. E-mail sebcal{at}unimo.it
Abstract—Seventy-one mutations of
the low density lipoprotein (LDL) receptor gene were identified in 282
unrelated Italian familial hypercholesterolemia
(FH) heterozygotes. By extending genotype analysis to
families of the index cases, we identified 12 mutation clusters and
localized them in specific areas of Italy. To evaluate the impact of
these mutations on the clinical expression of FH, the clusters were
separated into 2 groups: receptor-defective and receptor-negative,
according to the LDL receptor defect caused by each mutation. These 2
groups were comparable in terms of the patients’ age, sex
distribution, body mass index, arterial hypertension, and
smoking status. In receptor-negative subjects, LDL
cholesterol was higher (+18%) and high density lipoprotein
cholesterol lower (-5%) than the values found in
receptor-defective subjects. The prevalence of tendon xanthomas and
coronary artery disease (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, arterial
hypertension, previous smoking, and LDL cholesterol level.
Independent contributors to CAD in the receptor-defective subjects were
male sex, arterial hypertension, and LDL
cholesterol level; in the receptor-negative subjects, 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 of receptor-defective subjects. Wide
interindividual variability in LDL cholesterol levels was
found in each cluster. Apolipoprotein E genotype
analysis showed a lowering effect of the 
2 allele and a
raising effect of the 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 clusters shared the same
intragenic haplotype cosegregating with the mutation, thus suggesting
the presence of common ancestors.
Key Words: LDL receptor gene mutations • familial hypercholesterolemia • mutation clusters • receptor phenotype and clinical expression
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