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LDL-receptor gene mutations and the hypocholesterolemic response to statin therapy
J U Brorholt-Petersen1, H K Jensen, B Raungaard
1Department of Internal Medicine and Cardiology, Aarhus Amtssygehus University Hospital, Tage-Hansens Gade 2, DK-8000 Aarhus C, Denmark. jubp@post3.tele.dk
Abstract:
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.
Insights
Statin therapy effectiveness for lowering cholesterol may depend on the specific low-density lipoprotein (LDL)-receptor mutation. This study found minor differences in fluvastatin response between mutation types, suggesting genetic background influences treatment outcomes.
Area of Science:
- Biochemistry
- Genetics
- Pharmacology
Background:
- Cholesterol-lowering effects of statins vary with low-density lipoprotein (LDL)-receptor mutation types.
- Previous studies lacked clarity due to mixed patient populations with diverse LDL-receptor mutations.
Purpose of the Study:
- To investigate if fluvastatin response differs between two specific LDL-receptor mutations: receptor-negative (Trp23-stop) and receptor-binding defective (Trp66-Gly).
- To test the hypothesis that statin treatment efficacy is mutation-dependent.
Main Methods:
- A double-blind, cross-over study involving 58 patients with heterozygous familial hypercholesterolemia.
- Patients received either 40 mg daily fluvastatin or placebo for 12 weeks, following an 8-week placebo run-in.
- Lipid and lipoprotein levels were measured to assess treatment response.
Main Results:
- Baseline lipid and lipoprotein concentrations were similar between the two mutation groups.
- A trend suggested a less pronounced cholesterol and LDL cholesterol reduction in receptor-binding defective patients, but this was not statistically significant.
- Analysis of current and prior studies indicated that mutation-specific statin response differences are more apparent in populations with recent genetic admixture.
Conclusions:
- The specific type of LDL-receptor mutation may influence statin response, although not significantly in this study.
- Genetic background, particularly in admixed populations, might play a role in statin efficacy by influencing uncharacterized genetic variations impacting drug metabolism.