Influence of LDL receptor gene mutation and apo E polymorphism on lipoprotein response to simvastatin treatment among adolescents with heterozygous familial hypercholesterolemia.
The efficacy of the inhibitors of HMG CoA reductase shows considerable interindividual variation and intense research has focused in the recent years to identify the genetic loci and environmental factors responsible for this variability. A randomized, double-blind, placebo-controlled clinical trial with simvastatin, an HMG CoA reductase inhibitor, was conducted in 63 adolescents (47 treated versus 17 controls) with heterozygous FH. The patients were grouped according to known low-density lipoprotein (LDL) receptor gene mutation class. After 6 weeks of treatment with 20 mg/d of simvastatin, the mean reduction in plasma LDL-cholesterol in patients with a receptor-negative mutation (n=33) was 39% whereas, in the receptor-defective mutation group (n=14), it was 31% (P=0.01). Multiple regression analyses showed that there was a significant association between the apo E polymorphism and LDL-cholesterol response to simvastatin only among heterozygotes for a receptor-negative mutation. In subjects carrying a receptor-defective mutation, however, we observed that 51% of the variability in LDL-cholesterol response was explained by variations in the dosage of simvastatin expressed in mg/kg/day (P=0.0028). There was no significant association between LDL-cholesterol response and the dosage of simvastatin among heterozygotes for a receptor-negative mutation. The results of the present study have shown that the contribution of apo E polymorphism and the dosage of simvastatin to the LDL-cholesterol responsiveness is influenced by the nature of the LDL receptor gene mutation.
Vohl
Marie Claude
MC
Lipid Research Center, Room S-102, CHUL Research Center, 2705 Laurier Blvd., Quebec, Canada G1V 4G2.
Szots
Francois
F
Lelièvre
Michel
M
Lupien
Paul J
PJ
Bergeron
Jean
J
Gagné
Claude
C
Couture
Patrick
P
D000293:Adolescent; D001057:Apolipoproteins E / Q000235:genetics*; D002648:Child; D008078:Cholesterol, LDL / Q000097:blood*; D004311:Double-Blind Method; D005260:Female; D006579:Heterozygote; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D009154:Mutation; D011110:Polymorphism, Genetic; D011973:Receptors, LDL / Q000235:genetics*; D019821:Simvastatin / Q000627:therapeutic use*
D001057:Apolipoproteins E; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011973:Receptors, LDL; D019821:Simvastatin