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Gene May Affect Response to Cholesterol-lowering Drug

By Cheryl Simon Silver

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A team of researchers looking at how genes may influence the body’s response to the cholesterol-lowering drugs reports that individuals with specific genetic variations may be less responsive to the drug pravastatin than individuals without the variants.

The finding currently has no immediate implications for doctors and patients, and there is no widely available genetic test for the variations. But the study, one of the largest of its type, is another example of how knowledge of a patient’s genetic makeup may someday help physicians select the most appropriate drugs.

Daniel Chasman of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues looked at ten genes known to be involved in cholesterol synthesis and metabolism. Over a 24-week period, they monitored blood samples from more than 1,500 individuals treated with pravastatin. The drug is often taken to reduce the amount of cholesterol and certain fatty substances in blood.

Individuals in the study with specific variations in one of the ten genes experienced a 22 percent smaller reduction in total cholesterol compared to those without the variation. Nearly everyone who had one of the variations in the gene, called HMG-CoA reductase, had the other variation as well.

The finding will need to be replicated in other populations, and the researchers say that it’s too soon to generalize these results to other statins. It could be that individuals with these gene variants might respond to a higher dose of pravastatin or to an alternative nonstatin, lipid-lowering drug.

The magnitude of the reduced response to the drug could have an effect on the number of heart attacks experienced across a population, according to Chasman.

Even so, a person’s lifestyle is still key. “We think that other factors, such as diet and exercise, contribute more to the variation in drug response than genetics, and swamp out the genetic effect,” he says.

A commentary accompanying the findings in the Journal of the American Medical Association notes that large-scale studies are needed if this area of research, known as pharmacogenetics, is to fulfill its promise.

Such large studies are “necessary to prevent changes in practice that are based on speculative or incomplete findings,” write Wylie Burke of the University of Washington in Seattle and Susanne Haga of the Center for the Advancement of Genomics in Rockville, Maryland.

Chasman agrees that large studies are important. “We do not think we would have found the effect if we had not looked at so many people,” he says.

D. Chasman et al. Pharmacogenetic Study of Statin Therapy and Cholesterol Reduction. JAMA. 291, pp. 2821-2827 (June 16, 2004).
S. Haga and W. Burke. Using Pharmacogenetics to Improve Drug Safety and Efficacy. JAMA. 291, pp. 2869-2871 (June 16, 2004).

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