title: Association of specific LDL receptor gene mutations with differential plasma lipoprotein response to simvastatin in young French Canadians with heterozygous familial hypercholesterolemia.
abstract: In familial hypercholesterolemia (FH), the efficacy of the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase shows considerable interindividual variation, and several genetic and environmental factors can contribute to explaining this variability. A randomized, double-blind, placebo-controlled clinical trial with simvastatin, an HMG-CoA reductase inhibitor, was conducted in 63 children and adolescents with heterozygous FH. The patients were grouped according to known LDL receptor genotype. After 6 weeks of treatment with 20 mg/d simvastatin, the mean reduction in plasma LDL cholesterol in patients with the W66G mutation (n=14) was 31%, whereas in the deletion>15 kb (n=23) and the C646Y mutation groups (n=10), it was 38% and 42%, respectively (P<0.05). After treatment with simvastatin, HDL cholesterol levels were increased in all groups, and triglyceride concentrations were significantly reduced. Multiple regression analyses suggested that 42% of the variation of the LDL cholesterol response to simvastatin can be attributed to variation in the mutant LDL receptor locus, apolipoprotein E genotype, and body mass index, while 35% of the variation in HDL cholesterol response was explained by sex and baseline HDL cholesterol. These results show that simvastatin was an effective and well-tolerated therapy for FH in the pediatric population for all LDL receptor gene mutations. Moreover, the nature of LDL receptor gene mutations and other genetic and constitutional factors play a significant role in predicting the efficacy of simvastatin in the treatment of FH in children and adolescents.
authors.affiliation: Department of Medicine, CHUL Research Center and Laval University, Québec, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Couture
authors.forename: L D
authors.initials: LD
authors.lastname: Brun
authors.forename: F
authors.initials: F
authors.lastname: Szots
authors.forename: M
authors.initials: M
authors.lastname: Lelièvre
authors.forename: D
authors.initials: D
authors.lastname: Gaudet
authors.forename: J P
authors.initials: JP
authors.lastname: Després
authors.forename: J
authors.initials: J
authors.lastname: Simard
authors.forename: P J
authors.initials: PJ
authors.lastname: Lupien
authors.forename: C
authors.initials: C
authors.lastname: Gagné
mesh_terms: D000293:Adolescent; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001055:Apolipoproteins B / Q000097:blood; D002170:Canada; D002648:Child; D008078:Cholesterol, LDL / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D006579:Heterozygote; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D008074:Lipoproteins / Q000097:blood*; D008297:Male; D017354:Point Mutation; D011973:Receptors, LDL / Q000235:genetics*; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D000924:Anticholesteremic Agents; D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008074:Lipoproteins; D011973:Receptors, LDL; D019821:Simvastatin