Abstract P526: PON1 Q192R Alters Clopidogrel Efficacy in Patients With Coiling of Intracranial Aneurysm but Not Carotid Artery Stenting

Abstract

Introduction: The impact of the paraoxonase-1 ( PON1 ) polymorphism, Q192R (rs662; c.575A>G or p.Gln192Arg), on platelet inhibition in response to clopidogrel remains controversial. We investigated the impact of PON1 Q192R on post-clopidogrel platelet reactivity in patients undergoing coil embolization for intracranial aneurysm (IA) and carotid artery stenting (CAS). Methods: Between May 2010 and September 2015, 567 patients undergoing elective neurointervention with dual antiplatelet therapy were registered. On-treatment platelet reactivity was measured using a VerifyNow P2Y12 assay in P2Y12 reaction units (PRUs). High platelet reactivity (HPR) was defined as a PRU of ≥208. Genotype testing was performed for PON1 Q192R and CYP2C19*2 and *3 (loss of function alleles), and *17 . Consequently, 473 patients were eligible for further analysis. For patients undergoing coil embolization for IA or CAS, associations between ≥1 PON1 192R allele and HPR were investigated. Results: HPR was observed in 59.4% of 276 patients undergoing coil embolization for IA (78 male; median age, 62 years) and 47.7% of 197 patients undergoing CAS (153 male; median age, 72 years). Among patients undergoing coil embolization for IA, carriers of ≥1 PON1 192R allele demonstrated HPR more frequently compared with non-carriers (92.1% vs. 83.0%, respectively; P = 0.021). Carrying ≥1 PON1 192R allele was associated with HPR (adjusted odds ratio [aOR] 3.43, 95% confidence interval [CI] 1.45-8.42). In contrast, among patients undergoing CAS, the frequency of HPR was similar between carriers of ≥1 PON1 192R allele compared with non-carriers (90.4% vs. 87.4%, respectively; P = 0.652). Carrying ≥1 PON1 192R allele was not associated with HPR (aOR 0.95, 95% CI 0.34-2.60). Conclusions: PON1 Q192R is associated with HPR of clopidogrel in patients undergoing coil embolization for IA but not in patients undergoing CAS. PON1 metabolizes clopidogrel into the inactive endo isomer. By contrast, PON1 protects against low-density lipoprotein oxidation. High PON1 activity may cancel the disadvantage in clopidogrel metabolism through its antioxidant and atheroprotective effects in patients carrying ≥1 PON1 192R allele with carotid artery stenosis representing advanced systemic atherosclerosis.