JAMA: Researchers home in on gene variant for Plavix responsiveness

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Using a novel technique and a group of people with stable genetic variability, researchers have confirmed that about one-third of the general population may carry a gene variant that plays a major role in determining the body’s response to clopidogrel (Plavix), according to a study in the Aug. 26 issue of the J ournal of the American Medical Association.

Researchers used for the first time a sophisticated technique called a genome-wide association to rapidly scan hundreds of thousands of genetic markers in the DNA of participants. The population in this study (Old Order Amish) are a relatively homogeneous group in which confounding variables, including medication usage and lifestyle, were minimized.

The investigators gave more than 400 healthy Amish participants clopidogrel for seven days and then looked at how their blood platelets responded.

"By scanning the entire genome, we found compelling evidence that the CYP2C19*2 gene is a key determinant of how people respond to this medication," said lead author Alan R. Shuldiner, MD, professor of medicine at the University of Maryland in Baltimore. Shuldiner said that their results suggest the response to clopidogrel is largely inherited.

University of Maryland investigators collaborated with researchers at the Sinai Center for Thrombosis Research in Baltimore, confirming their findings by studying a group of 227 people who received clopidogrel after undergoing PCI at Sinai Hospital. Patients with the gene variant were more likely (20.9 vs. 10 percent) to have a heart attack or other serious cardiovascular event in the year following initiation of treatment.

“The results of the study lend support to genotyping and platelet function testing as potential future strategies for optimal antiplatelet drug selection in treating patients with cardiovascular disease," said senior author Paul A. Gurbel, MD, director of the Sinai Center for Thrombosis Research.

The authors wrote that those with the CYP2C19*2 genotype may benefit more from an antiplatelet regimen that “does not include clopidogrel, such as the third-generation thienopyridine prasugrel, or ticagrelor and cangrelor,” adding that these agents are not as dependent on CYP2C19*2 for platelet activation as is clopidogrel.

They said that “genotype-directed decisions regarding which antiplatelet agent to use in a specific patient may also have an important economic impact if costs of equally efficacious medications differ greatly.”

Shuldiner and colleagues said that it is unknown whether CYP2C19*2 carriers may benefit from increased dosing of clopidogrel.