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June 16, 2004

Using Pharmacogenetics to Improve Drug Safety and Efficacy

Author Affiliations

Author Affiliations: The Center for the Advancement of Genomics, Rockville, Md (Dr Haga); Department of Medical History and Ethics, University of Washington, Seattle (Dr Burke).

JAMA. 2004;291(23):2869-2871. doi:10.1001/jama.291.23.2869

Pharmacogenetics, the tailoring of drug treatment according to individual genotype, has been widely proclaimed as a first step toward personalized medicine. In this issue of THE JOURNAL, Chasman et al1 report the association of 2 common polymorphisms in the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) gene with reduced efficacy of pravastatin therapy. In a survey of 148 single nucleotide polymorphisms in 10 genes involved in lipid metabolism, carriers of 2 linked SNPs in the HMGCR gene showed significantly smaller reductions in levels of cholesterol, triglycerides, and low-density lipoprotein cholesterol with treatment. Statins, the most potent and widely used cholesterol-lowering drugs, function as competitive inhibitors of HMGCR, the rate-limiting enzyme for cholesterol synthesis. This study is the first to demonstrate the impact of genetic variation in the HMGCR drug target for this popular class of drugs, justifying the need for further study to validate and perhaps translate these findings into the clinical setting.

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