Gene Variant Can Dampen Effect of Antiplatelet Therapy

Gene reduces clopidogrel's ability to inhibit ADP-stimulated platelet activation

TUESDAY, Aug. 25 (HealthDay News) -- Clopidogrel's effectiveness in antiplatelet therapy for patients with acute coronary syndromes or those who have had percutaneous coronary intervention (PCI) can be dampened for those who have the CYP2C19*2 gene variant, according to a study in the Aug. 26 issue of the Journal of the American Medical Association.

Alan R. Shuldiner, M.D., of the University of Maryland School of Medicine in Baltimore, and colleagues administered clopidogrel to 429 healthy Amish people and evaluated the drug's response by using platelet aggregometry. The researchers then performed a genome-wide association study followed by genotyping of the cytochrome P450 (CYP) 2C19*2 variant (rs4244285) to discover associations for those in whom clopidogrel effectiveness was impaired. In addition, the researchers studied the CYP2C19*2 genotype and cardiovascular outcomes in 227 patients who underwent PCI.

The researchers identified 13 single-nucleotide polymorphisms on chromosome 10q24 in the CYP2C18-CYP2C19-CYP2C9-CYP2C8 cluster that were linked to reduced clopidogrel response in the Amish cohort. A similar relation between CYP2C19*2 genotype and platelet aggregation also was seen in clopidogrel-treated patients undergoing coronary intervention. In one year follow-up, 20.9 percent of the clopidogrel-treated PCI patients with the CYP2C19*2 variant had a cardiovascular ischemic event or death compared to 10 percent without the variant.

"We report the first genome-wide association study of clopidogrel response and show that the common loss-of-function CYP2C19*2 variant is a major determinant of adenosine diphosphate-stimulated platelet aggregation. Individuals with this genotype have reduced protection from clopidogrel in preventing cardiovascular disease-related events following PCI," the authors write.

One study author reported being involved in a patent application for anti-thrombotic agents, and a second study author reported receiving honoraria and consulting fees from several pharmaceutical companies.

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