LDL-receptor gene mutations and the hypocholesterolemic response to statintherapy

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 differ ent kinds of LDL-receptor mutations. We studied the response to treatment w ith fluvastatin in 28 patients with heterozygous familial hypercholesterole mia as a result of a receptor-negative mutation (Trp23-stop) and in 30 pati ents with a receptor-binding defective mutation (Trp66-Gly) to test the hyp othesis that response to treatment depends on the type of mutation. Patient s 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 we eks in a double-blind, cross-over design. Untreated plasma concentrations o f lipids and lipoproteins were similar in the two groups of patients. Plasm a cholesterol and LDL cholesterol response to therapy tended to be less mar ked in receptor-binding defective patients, but the differences were not st atistically significant. A tabulation of the results of the present and ear lier 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 w ith the same mutation in the LDL-receptor gene are more likely to share oth er but undetermined genetic variations affecting the pharmacology of statin s.