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Genetic Variation in Response to Statin Therapy

The cholesterol-lowering effect of statins can vary according to patients' genetic profiles.

Statins substantially reduce total- and LDL-cholesterol levels in most patients, but individuals vary in their response. To examine whether genetic differences account for some of this variation, researchers analyzed the DNA of 1536 subjects (35% women) who had received 40 mg/day of pravastatin as part of the PRINCE randomized trial. Specifically, they considered 148 single-nucleotide polymorphisms (SNPs) in 10 candidate genes that are important in cholesterol synthesis and statin metabolism. Genetic variations were compared with changes in lipid levels in response to pravastatin therapy over 6 months.

Two SNPs (SNP 12 and SNP 29) that code for 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the target enzyme that pravastatin inhibits, showed a link with pravastatin efficacy. For each of these SNPs, subjects who were heterozygous for the major allele showed total-cholesterol reductions that were 22% smaller, and LDL-cholesterol reductions that were 19% smaller, than reductions in homozygous subjects. These findings persisted after correction for all 148 SNPs evaluated, in both men and women, and in white subjects (who were 89% of the cohort).

Comment: People who were heterozygous for a variant in the HMG-CoA reductase gene experienced significantly smaller cholesterol-lowering benefits of pravastatin than did homozygous patients. Further studies must confirm this finding. As the editorialists note, pharmacogenetics might eventually help to identify the most appropriate candidates for particular pharmacologic interventions such as statin therapy. However, whether such an approach would improve clinical outcomes is unclear.

— JoAnne M. Foody, MD

Published in Journal Watch Cardiology August 6, 2004

Citation(s):

Chasman DI et al. Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA 2004 Jun 16; 291:2821-7.

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• Medline abstract (Free)

Haga SB and Burke W. Using pharmacogenetics to improve drug safety and efficacy. JAMA 2004 Jun 16; 291:2869-71.

• Original article (Subscription may be required)
• Medline abstract (Free)