Besides CYP2C192, the variant allele CYP2C93 is associated with higher on-clopidogrel platelet reactivity in patients on dual antiplatelet therapy undergoing elective coronary stent implantation

• Published in: Pharmacogenetics and genomics Vol. 20; no. 1; p. 18
• Main Authors: Harmsze, Ankie, van Werkum, Jochem W, Bouman, Heleen J, Ruven, Henk J, Breet, Nicolien J, Ten Berg, Jurrien M, Hackeng, Christian M, Tjoeng, Mathieu M, Klungel, Olaf H, de Boer, Anthonius, Deneer, Vera H
• Format: Journal Article
• Language: English
• Published: United States 01.01.2010
• Subjects: Alleles; Aryl Hydrocarbon Hydroxylases - genetics; Blood Platelets - drug effects; Coronary Disease - drug therapy; Coronary Disease - therapy; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C9; Dose-Response Relationship, Drug; Female; Genetic Variation - genetics; Genotype; Haplotypes; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors - pharmacology; Platelet Aggregation Inhibitors - therapeutic use; Platelet Function Tests; Prospective Studies; Stents; Ticlopidine - analogs & derivatives; Ticlopidine - pharmacokinetics; Ticlopidine - pharmacology; Ticlopidine - therapeutic use
• ISSN: 1744-6880
• DOI: 10.1097/FPC.0b013e328333dafe

The prodrug, clopidogrel, plays an important role in the prevention of thrombotic events in patients undergoing coronary stenting. However, a substantial number of atherothrombotic events still occur, which can partially be explained by heightened residual platelet reactivity. Several studies report that the genetic variation in CYP2C19 (*2) is associated with an impaired response to clopidogrel. To evaluate the effect of genetic variants affecting clopidogrel's absorption (ABCB1 C1236T, G2677T/A, C3435T), metabolism (CYP2C9*2, *3, CYP2C19*3, CYP3A4*1B, and CYP3A5*3), and pharmacodynamics (P2Y1 A1622G) on top of the influence of CYP2C19*2 on platelet reactivity in patients undergoing elective coronary stenting on dual antiplatelet therapy. Platelet function was assessed by light transmittance aggregometry and VerifyNow P2Y12 assay in 428 consecutive patients. Patients were either on chronic clopidogrel maintenance therapy (75 mg/day for > or =5 days before the intervention) or received a 300 mg clopidogrel loading dose (1-5 days before the intervention, followed by 75 mg/day). Linear and logistic regressions were used to assess the associations between genetic variants and platelet reactivity and poor responder status. In both the treatment groups, CYP2C19*2-carriage was associated with higher platelet reactivity (P<0.002) and poor responder status; 75 mg group: adjusted odds ratio (ORadj): 3.8, 95% confidence interval (CI): 2.0-7.2, 300 mg group: ORadj: 4.1, 95% CI: 1.6-10.4. In the 300 mg group, CYP2C9*3-carriage was associated with higher platelet reactivity (P<0.05) and poor responder status (ORadj: 11.1, 95% CI: 1.6-78.8, P=0.016). Besides CYP2C19*2, the variant allele CYP2C9*3 plays an important role in the response to clopidogrel in patients on dual antiplatelet therapy undergoing coronary stenting.