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Effect of low-density lipoprotein receptor mutation on lipoproteins and cardiovascular disease risk: a

Kristel C M C Koeijvoets1, Albert Wiegman, Jessica Rodenburg

  • 1Department of Internal Medicine, Erasmus Medical Centre-D435, P.O. Box 2040, 3000 AC Rotterdam, The Netherlands.

Atherosclerosis
|April 13, 2005
PubMed

Insights

Children with familial hypercholesterolemia (FH) offer a clearer model for genotype-phenotype analysis. Null LDL receptor alleles in children significantly increase LDL cholesterol but do not elevate parental cardiovascular disease risk.

Area of Science:

  • Genetics
  • Cardiology
  • Pediatrics

Background:

  • Clinical consequences of low-density lipoprotein (LDL) receptor genotypes in adults with familial hypercholesterolemia (FH) show conflicting results.
  • Investigating genotype-phenotype correlations in pediatric FH may provide a more robust model for analysis.

Purpose of the Study:

  • To assess the effect of LDL receptor genotypes on lipoprotein levels in children with FH.
  • To evaluate the impact of these genotypes on the risk of cardiovascular disease (CVD) in the parents of these children.

Main Methods:

  • Identified 75 different LDL receptor mutations in 645 children with heterozygous FH.
  • Analyzed lipoprotein levels and parental CVD risk based on identified mutations, comparing null alleles with receptor-defective mutations.

Main Results:

  • Null LDL receptor alleles were associated with significantly higher LDL cholesterol levels in children compared to receptor-defective mutations.
  • Familial factors explained a substantial portion of LDL cholesterol variation in the pediatric cohort (50.4%) versus adults (9.5%).
  • Parental CVD risk did not significantly differ between carriers of null and receptor-defective mutations. However, the N543H/2393del9 mutation was linked to milder lipid profiles and reduced parental CVD risk.

Conclusions:

  • Children with FH serve as a superior model for genotype-phenotype studies compared to adults.
  • While null LDL receptor alleles in children elevate LDL cholesterol, they do not increase parental CVD risk.
  • A specific LDL receptor mutation (N543H/2393del9) demonstrates a protective effect, correlating with improved lipid profiles and lower CVD risk in parents.

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