Abstract 9551: Relative Contributions of Genetic Variants in PON1, CYP2C19 And ABCB1 on in-hospital and One Year Clinical Outcomes in Patients Treated with Clopidogrel After an Acute Myocardial Infarction
Background: Clopidogrel with aspirin reduces ischemic events in patients with acute myocardial infarction (AMI). Clopidogrel requires drug transport via P-glycoprotein, encoded by ABCB1, and bioactivation by CYP450, mainly via CYP2C19. The clinical response to clopidogrel is variable, depending in part on CYP2C19 and ABCB1 genetic polymorphisms. Recently however, paraoxonase-1 (PON1) was suggested as the crucial enzyme for clopidogrel bioactivation, with its Q192R polymorphism determining per se clopidogrel response on cardiovascular events.
Methods We assessed the effect of PON1(Q192R) polymorphisms by itself and alongside variants in CYP2C19 loss-of-function and ABCB1 on in-hospital and one-year cardiovascular events in clopidogrel-treated AMI patients participating in the Fast-MI study (n=2208), including the subset undergoing PCI (n=1538).
Results : PON1(Q192R) polymorphism was not associated with increased risk of in-hospital death and one year major adverse events: One-year adjusted hazard ratio [HR] for QQ versus RR individuals, 1.03; 95% CI, 0.66-1.61 in the whole population and HR, 0.77; 95% CI, 0.42-1.41 in PCI-treated patients. Adding ABCB1 and CYP2C19 polymorphisms had no impact on these risks. Presence of two CYP2C19 loss-of-function alleles was associated with the risk of in-hospital death and major clinical events at one year in the overall population (OR: 3.67; 95% CI, 1.05-12.80, and HR: 1.96, 95% CI, 1.08-3.54) and in PCI patients (OR, 6.87; 95% CI, 2.52-18.72, and HR: 3.06, 95% CI, 1.47-6.41). ABCB1 polymorphisms had an impact on the clinical response to clopidogrel in the overall population but not in PCI patients.
Conclusion : PON1 polymorphism was not associated with an increased risk of events in clopidogrel-treated patients with AMI and those undergoing PCI. In contrast, CYP2C19 loss- -of-function polymorphism remained the major pharmacogenetic contributor of clinical response to clopidogrel in these populations.
- © 2011 by American Heart Association, Inc.