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Daniel I. Chasman, PhD; David Posada, PhD; Lakshman Subrahmanyan, MS; Nancy R. Cook, PhD; Vincent P. Stanton, Jr, MD; Paul M Ridker, MD, MPH

JAMA. 2004;291:2821-2827.

Context  Polymorphisms in genes involved in cholesterol synthesis, absorption, and transport may affect statin efficacy.

Objective  To evaluate systematically whether genetic variation influences response to pravastatin therapy.

Design, Setting, and Population  The DNA of 1536 individuals treated with pravastatin, 40 mg/d, was analyzed for 148 single-nucleotide polymorphisms (SNPs) within 10 candidate genes related to lipid metabolism. Variation within these genes was then examined for associations with changes in lipid levels observed with pravastatin therapy during a 24-week period.

Main Outcome Measure  Changes in lipid levels in response to pravastatin therapy.

Results  Two common and tightly linked SNPs (linkage disequilibrium r² = 0.90; heterozygote prevalence = 6.7% for both) were significantly associated with reduced efficacy of pravastatin therapy. Both of these SNPs were in the gene coding for 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the target enzyme that is inhibited by pravastatin. For example, compared with individuals homozygous for the major allele of one of the SNPs, individuals with a single copy of the minor allele had a 22% smaller reduction in total cholesterol (–32.8 vs –42.0 mg/dL [–0.85 vs –1.09 mmol/L]; P = .001; absolute difference, 9.2 mg/dL [95% confidence interval {CI}, 3.8-14.6 mg/dL]) and a 19% smaller reduction in low-density lipoprotein (LDL) cholesterol (–27.7 vs –34.1 mg/dL [–0.72 vs –0.88 mmol/L]; P = .005; absolute difference, 6.4 mg/dL [95% CI, 2.2-10.6 mg/dL]). The association for total cholesterol reduction persisted even after adjusting for multiple tests on all 33 SNPs evaluated in the HMG-CoA reductase gene as well as for all 148 SNPs evaluated was similar in magnitude and direction among men and women and was present in the ethnically diverse total cohort as well as in the majority subgroup of white participants. No association for either SNP was observed for the change in high-density lipoprotein (HDL) cholesterol (P>.80) and neither was associated with baseline lipid levels among those actively treated or among those who did not receive the drug. Among the remaining genes, less robust associations were found for squalene synthase and change in total cholesterol, apolipoprotein E and change in LDL cholesterol, and cholesteryl ester transfer protein and change in HDL cholesterol, although none of these met our conservative criteria for purely pharmacogenetic effects.

Conclusion  Individuals heterozygous for a genetic variant in the HMG-CoA reductase gene may experience significantly smaller reductions in cholesterol when treated with pravastatin.

Author Affiliations: Center for Cardiovascular Disease Prevention, the Donald W. Reynolds Center for Cardiovascular Research, and the Leducq Center for Molecular and Genetic Epidemiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass (Drs Chasman, Cook, and Ridker); and the former Variagenics Inc, Cambridge, Mass (Drs Chasman, Posada, and Stanton and Mr Subrahmanyan). Dr Posada is now with the Department of Biochemistry, Genetics, and Immunology, University of Vigo, Vigo, Spain.

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