Genetic determinants of responsiveness to the HMG-CoA reductase inhibitor fluvastatin in patients with molecularly defined heterozygous familial hypercholesterolemia.
BACKGROUND
In familial hypercholesterolemia, plasma lipoproteins can be modulated by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, although the underlying response mechanisms are still unknown.


RESULTS
A single-blind study with fluvastatin, an HMG-CoA reductase inhibitor, was conducted in 64 familial hypercholesterolemia patients who had defined apolipoprotein E (apo E) and apolipoprotein(a) [apo(a)] isoforms. Plasma lipids and lipoproteins were analyzed throughout the study. The patients were grouped according to low density lipoprotein (LDL) receptor genotype. After 4 weeks of treatment with 40 mg of fluvastatin, the mean decrease in plasma LDL cholesterol (LDL-C) in patients with the genetically characterized "Sephardic" and "Lithuanian" mutations was 16-18%, whereas in the other three groups, it was 25-30% (p < 0.005). High density lipoprotein cholesterol (HDL-C) levels increased in all groups. Multivariate analyses suggested that 41% of the LDL-C response can be explained by the LDL receptor mutation, body mass index, apo E3/E4 phenotype, apo(a) isoform LpS2, and baseline LDL-C levels, and 46% of the change in HDL-C is associated with age, sex, body mass index, baseline HDL-C, and the Sephardic mutation.


CONCLUSIONS
Fluvastatin exhibits diverse and independent effects on plasma lipoproteins related to several constitutional, genetic, and familial factors. Information regarding these factors may provide better prediction of patients' clinical responses to fluvastatin.
Leitersdorf
E
E
Department of Medicine, Hadassah University Hospital, Jerusalem, Israel.
Eisenberg
S
S
Eliav
O
O
Friedlander
Y
Y
Berkman
N
N
Dann
E J
EJ
Landsberger
D
D
Sehayek
E
E
Meiner
V
V
Wurm
M
M
D000328:Adult; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D005229:Fatty Acids, Monounsaturated / Q000627:therapeutic use*; D005260:Female; D000077340:Fluvastatin; D006579:Heterozygote; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006938:Hyperlipoproteinemia Type II / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics*; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D015999:Multivariate Analysis; D009154:Mutation; D011973:Receptors, LDL / Q000235:genetics; D016037:Single-Blind Method
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D011973:Receptors, LDL; D000077340:Fluvastatin