Paraoxonase 1 Gene Polymorphism Does Not Affect Clopidogrel Response Variability but Is Associated with Clinical Outcome after PCI

BACKGROUND Paraoxonase (PON) is a high-density-lipoprotein (HDL) associated enzyme with antioxidative and anti-atherogenic property. Its function is associated with coronary artery disease and its activity genetically controlled. We evaluated whether genetic variation of PON-1 is associated with clinical outcome in a large cohort of Korean patients with drug-eluting stents implantation. METHODS A total of 1676 patients with drug-eluting stent implantation were enrolled in the prospective CROSS-VERIFY cohort from June 2006 to June 2010. We genotyped the PON1-Q192R gene, measured clopidogrel on-treatment platelet reactivity (OPR), and analyzed lipid profiles. The primary endpoint was the composite of cardiac death, myocardial infarction, and stent thrombosis at 12 months. RESULTS PON-1 genotyping data were available in 1336 patients. Since the Q-allele is associated with decreased PON-activity, we analyzed the outcome between patients with QQ/QR (815 patients, 61%) and those with RR-genotype (521 patients, 39%). After adjustment for common cardiac risk factors, the QQ/QR-genotype was an independent predictor of the primary thrombotic endpoint with an 11-fold increased risk (HR 11.6, 95% CI: 1.55-87.0), but not repeat revascularization (HR 1.12, 95% CI: 0.78-1.61). The QQ/QR-genotype was not associated with OPR (QQ/QR: 231±86 PRU vs. RR 236±82 PRU, p = 0.342) but higher small-dense LDL levels (1.20±0.12 mg/dL vs. 0.76±0.15 mg/dL, p = 0.027). The increased risk of thrombotic outcomes was more profound in acute coronary syndrome (ACS) patients compared with non-ACS patients. CONCLUSION PON1 Q-allele is an independent predictor of worse cardiovascular outcome independent of platelet function and is associated with significantly higher levels of small dense LDL-C.