title: Effect of low-density lipoprotein receptor mutation on lipoproteins and cardiovascular disease risk: a parent-offspring study.
abstract: Studies on the clinical consequences of different low-density lipoprotein (LDL) receptor genotypes in adult patients have yielded conflicting results. We hypothesized that children with familial hypercholesterolemia (FH) provide a better model to perform genotype-phenotype analyses than adults. We tested this hypothesis and assessed the effect of LDL receptor genotypes on lipoprotein levels and on parental risk of cardiovascular disease (CVD) in a pediatric FH cohort. We identified 75 different LDL receptor mutations in 645 children with heterozygous FH; in these children, null alleles were clearly associated with more elevated LDL cholesterol levels compared to receptor-defective mutations. Familial factors explained 50.4% of the variation in LDL cholesterol levels of this pediatric cohort compared to only 9.5% in adults. Parental CVD risk was not significantly different between carriers of null alleles and receptor-defective mutations (RR, 1.22; 95% CI, 0.76-1.95; p=0.4). The N543H/2393del9 mutation was associated with a less deteriorated lipid profile and the parents had less often CVD relative to parents with other mutations (RR, 0.39; 95% CI, 0.20-0.78; p=0.008). We could confirm that children with FH provide a better model to perform genotype-phenotype analyses. In particular, children with null alleles had significantly more elevated LDL cholesterol levels than carriers of other alleles but this was not associated with higher risk of CVD in the parents. Nonetheless, a specific LDL receptor mutation was associated with less deteriorated lipoprotein levels and a milder CVD risk.
authors.affiliation: Department of Internal Medicine, Erasmus Medical Centre-D435, P.O. Box 2040, 3000 AC Rotterdam, The Netherlands.
authors.forename: Kristel C M C
authors.initials: KC
authors.lastname: Koeijvoets
authors.forename: Albert
authors.initials: A
authors.lastname: Wiegman
authors.forename: Jessica
authors.initials: J
authors.lastname: Rodenburg
authors.forename: Joep C
authors.initials: JC
authors.lastname: Defesche
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: Eric J G
authors.initials: EJ
authors.lastname: Sijbrands
mesh_terms: D000293:Adolescent; D000328:Adult; D001161:Arteriosclerosis / Q000453:epidemiology* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005838:Genotype; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000453:epidemiology* / Q000235:genetics*; D008074:Lipoproteins / Q000097:blood; D008297:Male; D010290:Parents; D010641:Phenotype; D011973:Receptors, LDL / Q000235:genetics*; D012307:Risk Factors
chemical_list: D008074:Lipoproteins; D011973:Receptors, LDL