PON1 Q192R is associated with high platelet reactivity with clopidogrel in patients undergoing elective neurointervention: A prospective single-center cohort study.

Kõji Tanaka ,Haruka Miyata,Tsuyoshi Ohta,Kazutaka Sonoda,Hidehisa Nishi,Izumi Nagata,Ryota Ishibashi,Noriko Isobe,Makoto Saka,Nobutake Sadamasa,Konosuke Furuta,Takuya Matsushita,Junpei Koge,Takuya Okata,Sadayoshi Watanabe,Ryo Yamasaki,Masanori Gomi,Shoji Matsumoto,Keitaro Matsuo,Gulibahaer Ainiding,K Iinuma ,Ichirō Nakahara ,Tsuyoshi Hashimoto ,Jun Ichi Kira

doi:10.1371/journal.pone.0254067

Kõji Tanaka , Haruka Miyata + Show 22 more

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https://doi.org/10.1371/journal.pone.0254067

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Abstract

The impact of the paraoxonase-1 (PON1) polymorphism, Q192R, on platelet inhibition in response to clopidogrel remains controversial. We aimed to investigate the association between carrier status of PON1 Q192R and high platelet reactivity (HPR) with clopidogrel in patients undergoing elective neurointervention. Post-clopidogrel platelet reactivity was measured using a VerifyNow® P2Y12 assay in P2Y12 reaction units (PRU) for consecutive patients before the treatment. Genotype testing was performed for PON1 Q192R and CYP2C19*2 and *3 (no function alleles), and *17. PRU was corrected on the basis of hematocrit. We investigated associations between factors including carrying ≥1 PON1 192R allele and HPR defined as original and corrected PRU ≥208. Of 475 patients (232 men, median age, 68 years), HPR by original and corrected PRU was observed in 259 and 199 patients (54.5% and 41.9%), respectively. Carriers of ≥1 PON1 192R allele more frequently had HPR by original and corrected PRU compared with non-carriers (91.5% vs 85.2%, P = 0.031 and 92.5% vs 85.9%, P = 0.026, respectively). In multivariate analyses, carrying ≥1 PON1 192R allele was associated with HPR by original (odds ratio [OR] 1.96, 95% confidence interval [CI] 1.03-3.76) and corrected PRU (OR 2.34, 95% CI 1.21-4.74) after adjustment for age, sex, treatment with antihypertensive medications, hematocrit, platelet count, total cholesterol, and carrying ≥1 CYP2C19 no function allele. Carrying ≥1 PON1 192R allele is associated with HPR by original and corrected PRU with clopidogrel in patients undergoing elective neurointervention, although alternative results related to other genetic polymorphisms cannot be excluded.

Highlights

Dual antiplatelet therapy (DAPT), most commonly with aspirin and clopidogrel, is regularly used for antiplatelet premedication to prevent thromboembolic complications following endovascular treatment
Carriers of 1 PON1 192R allele more frequently had high platelet reactivity (HPR) by original and corrected P2Y12 reaction units (PRU) compared with noncarriers (91.5% vs 85.2%, P = 0.031 and 92.5% vs 85.9%, P = 0.026, respectively)
In multivariate analyses, carrying 1 PON1 192R allele was associated with HPR by original and corrected PRU after adjustment for age, sex, treatment with antihypertensive medications, hematocrit, platelet count, total cholesterol, and carrying 1 CYP2C19 no function allele

Summary

Introduction

Dual antiplatelet therapy (DAPT), most commonly with aspirin and clopidogrel, is regularly used for antiplatelet premedication to prevent thromboembolic complications following endovascular treatment. There is marked inter-patient variability of platelet inhibition in response to clopidogrel, and high platelet reactivity (HPR) with clopidogrel is associated with an increased risk of thromboembolic complications following endovascular treatment [1,2,3]. Carrying 1 CYP2C19 no function allele was associated with HPR with clopidogrel and thromboembolic complications following endovascular treatment [4,5,6]. CYP2C19 17 is an increased function SNP that contributes to enhanced platelet inhibition in response to clopidogrel [7]. The impact of the paraoxonase-1 (PON1) polymorphism, Q192R, on platelet inhibition in response to clopidogrel remains controversial. We aimed to investigate the association between carrier status of PON1 Q192R and high platelet reactivity (HPR) with clopidogrel in patients undergoing elective neurointervention

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