Therapy with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) lowers total and low-density lipoprotein (LDL) cholesterol and has proven to be highly effective for cardiovascular risk reduction, according to background information in the article. However, there is wide variation in interindividual response to statin therapy, and it has been hypothesized that genetic differences may contribute to this variation.
Daniel I. Chasman, Ph.D., of Brigham and Women's Hospital and Harvard Medical School, Boston, and colleagues conducted a study to determine whether common genetic variants influence the degree of lipid level reduction during pravastatin therapy. The study included 1,536 individuals treated with pravastatin, 40 mg/per day. Their DNA in blood samples 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.
"In this analysis of 148 SNPs across 10 genes known to be involved in cholesterol synthesis and statin metabolism, we found 2 common and closely linked polymorphisms in the HMG-CoA reductase gene that were significantly associated with a 22 percent smaller reduction in total cholesterol and a 19 percent smaller reduction in LDL cholesterol following 24 weeks of pravastatin therapy," the authors write. "For total cholesterol, these effects remained significant after adjustment for all SNPs evaluated and were consistent in magnitude and direction among men and women and among whites as well as the total cohort."
"We recognize that these data have considerable pathophysiologic interest and provide strong clinical evidence that there may be promise in the concept of 'personalized medicine' and the use of genetic screening to target certain therapies. The absolute difference in total cholesterol reduction associated with the HMG-CoA reductase genotype in our data was 9 mg/dL (0.23 mmol/L), an effect large enough to affect health on a population basis. Future studies must determine whether this difference can be offset by dose adjustment or the choice of an alternative nonstatin lipid-lowering therapy. In the meantime, clinical reminders to take treatment daily and to titrate dose as necessary to achieve National Cholesterol Education Program goals remain critical issues for practice," the authors conclude. (JAMA. 2004; 291:2821-2827. Available post-embargo at JAMA.com)
Editor's Note: Components of this work were supported by grants from the National Heart, Lung, and Blood Institute, the Doris Duke Charitable Foundation (New York, N.Y.), the Fondation Leducq (Paris), the Donald W. Reynolds Foundation (Las Vegas), and Bristol-Myers Squibb. Authors Chasman, Posada, Stanton and Subrahmanyan were employees of Variagenics Inc. when this project was initiated. Dr. Ridker received research support from Variagenics Inc. for portions of this work. Variagenics Inc. no longer exists.
COMMENTARY: USING PHARMACOGENETICS TO IMPROVE DRUG SAFETY AND EFFICACY
In an accompanying commentary, Susanne B. Haga, Ph.D., of the Center for the Advancement of Genomics, Rockville, Md., and Wylie Burke, M.D., Ph.D., of the University of Washington, Seattle, write that assessing the clinical implications of pharmacogenetic research will be a complex task.
"The individual response to drugs is multifactorial, due to interactions between extrinsic (e.g., environment, lifestyle) and intrinsic (e.g., sex, underlying disease, genetic predisposition) factors. Pharmacogenetic studies on drug-target interaction (pharmacodynamics) or drug metabolism (pharmacokinetics) are already yielding substantial information about the influence of genetic variation on drug response. However, the clinical use of such information--tailoring treatment of the individual patient based on genotype--must be based on empirical evidence that pharmacogenetic tests improve health outcomes."
The authors add that "by guiding drug therapy, pharmacogenetic testing could help to prevent serious injuries, hospitalization, mortality, and health care costs associated with adverse drug responses, and avoid the cost and inconvenience of prescribing drugs to patients who are likely to be nonresponders."
"Although the health outcomes of pharmacogenetics are untested, this technology has the potential to improve the safety and efficacy of commonly used drugs. An efficient research program could yield benefits in a relatively short period, representing a substantial contribution to the public's health. But neither market forces nor academic incentives are likely to produce the quality or type of data needed to proceed with confidence. An active effort is needed to ensure a rigorous assessment of this promising application of genomic technology, through partnerships and collaborative efforts among the federal, academic, and private sectors or, possibly, enhanced regulations," they conclude. (JAMA. 2004; 291:2869-2871. Available post-embargo at JAMA.com)
Editor's Note: This work was supported in part by a grant from the National Human Genome Research Institute and the University of Washington Center for Ecogenetics and Environmental Health and by a grant from the National Institute for Environmental Health Sciences. Dr. Haga owns stock in Pfizer Inc., Wyeth, Corixa Corp., Chiron Corp., Human Genome Sciences Inc., Agilent Technologies, Incara Pharmaceuticals, Array BioPharma, and Peregrine Pharmaceuticals.
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