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CYP2C19*2 variant linked with diminished platelet response to clopidogrel
The loss of function of the cytochrome P450 2C19*2 genotype — also known as rs4244285 — was associated with a diminished platelet response to clopidogrel treatment and poor cardiovascular outcomes, according to the results of a genome-wide association study.
“CYP2C19 genotype may prove useful in helping clinicians choose the most effective antiplatelet therapy and dose for a given individual,” researchers from the the Pharmacogenetics of Antiplatelet Intervention (PAPI) study wrote. “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 [Effient, Eli Lilly], or ticagrelor and cangrelor. Like clopidogrel, these agents inhibit adenosine diphosphate-stimulated platelet aggregation but are not as dependent on CYP2C19 for activation.”
Four hundred and twenty-nine healthy Amish participants were enrolled in the PAPI study. Patients were given clopidogrel for seven days. After seven days, a genome-wide association study was performed followed by genotyping the loss-of-function cytochrome P450 (CYP) 2C19*2 variant. Patient response was measured with ex vivo platelet aggregometry. The researchers compared the results of the association study to results from an independent sample of 227 patients undergoing percutaneous contrary intervention.
Two studies examining the interaction between the CYP2C19 gene and clopidogrel were published earlier this year in The New England Journal of Medicine.
Platelet response to clopidogrel was highly inheritable (P<.001). There were 13 single nucleotide polymorphisms across 1.5 megabases on the 10q24 chromosome associated with diminished response to clopidogrel (P<10–7). Twelve percent of the found variation in platelet aggregation to ADP was associated with a linkage disequilibrium between the rs12777823 polymorphism and the CYP2C19*2 variant.
ADP-stimulated platelet aggregation after clopidogrel administration was lower than baseline in participants with zero (reduced to 40.7%), one (reduced to 47.1%) or two (reduced to 65.4%) CYP2C19*2 alleles. In addition, patients with the CYP2C19*2 variant were more than twice as likely to have a cardiovascular ischemic event or die during the one-year follow-up period compared with patients without the variant (20.9% vs. 10.0%; HR=2.4; 95% CI, 1.18-4.99).
In an accompanying editorial, Deepak L. Bhatt, MD, director of the integrated cardiovascular program at Brigham and Women’s Hospital in Boston, Mass., commended the study’s researchers for helping to expand research in the area of pharmacogenetics testing for the tailoring of antiplatelet therapy to individual patients.
“Strides toward individualized therapy have already been made in cancer care and human immunodeficiency virus treatment,” Bhatt wrote in the editorial. “Antiplatelet therapy seems well suited to a tailored approach, and future investigations should pursue this promising area.”
Shuldiner A. JAMA. 2009;302:849-858.
