LDL-receptor gene mutations and the hypocholesterolemic response to statin therapy.
Studies of the cholesterol lowering effect of statin therapy as a function of low-density lipoprotein (LDL)-receptor mutation type have not produced a clear picture, possibly because they included patients with several different kinds of LDL-receptor mutations. We studied the response to treatment with fluvastatin in 28 patients with heterozygous familial hypercholesterolemia as a result of a receptor-negative mutation (Trp23-stop) and in 30 patients with a receptor-binding defective mutation (Trp66-Gly) to test the hypothesis that response to treatment depends on the type of mutation. Patients were randomized to 12 weeks of treatment with fluvastatin 40 mg daily and 12 weeks of placebo treatment, preceded by a placebo run-in period of 8 weeks in a double-blind, cross-over design. Untreated plasma concentrations of lipids and lipoproteins were similar in the two groups of patients. Plasma cholesterol and LDL cholesterol response to therapy tended to be less marked in receptor-binding defective patients, but the differences were not statistically significant. A tabulation of the results of the present and earlier studies suggests that differences in treatment response as an apparent function of LDL-receptor gene mutational type occur mainly in populations with recent genetic admixture (<400 years). In such populations, persons with the same mutation in the LDL-receptor gene are more likely to share other but undetermined genetic variations affecting the pharmacology of statins.
Brorholt-Petersen
J U
JU
Department of Internal Medicine and Cardiology, Aarhus Amtssygehus University Hospital, Tage-Hansens Gade 2, DK-8000 Aarhus C, Denmark. jubp@post3.tele.dk
Jensen
H K
HK
Raungaard
B
B
Gregersen
N
N
Faergeman
O
O
D000328:Adult; D000368:Aged; D015992:Body Mass Index; D002784:Cholesterol / Q000097:blood*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005229:Fatty Acids, Monounsaturated / Q000627:therapeutic use*; D005260:Female; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011973:Receptors, LDL / Q000235:genetics*; D016896:Treatment Outcome
D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D011973:Receptors, LDL; D000077340:Fluvastatin; D002784:Cholesterol