title: Effects of cytochrome P450 2C19 and paraoxonase 1 polymorphisms on antiplatelet response to clopidogrel therapy in patients with coronary artery disease.
abstract: Clopidogrel is an antiplatelet prodrug that is recommended to reduce the risk of recurrent thrombosis in coronary artery disease (CAD) patients. Paraoxonase 1 (PON1) is suggested to be a rate-limiting enzyme in the conversion of 2-oxo-clopidogrel to active thiol metabolite with inconsistent results. Here, we sought to determine the associations of CYP2C19 and PON1 gene polymorphisms with clopidogrel response and their role in ADP-induced platelet aggregation. Clopidogrel response and platelet aggregation were determined using Multiplate aggregometer in 211 patients with established CAD who received 75 mg clopidogrel and 75-325 mg aspirin daily for at least 14 days. Polymorphisms in CYP2C19 and PON1 were genotyped and tested for association with clopidogrel resistance. Linkage disequilibrium (LD) and their epistatic interaction effects on ADP-induced platelet aggregation were analysed. The prevalence of clopidogrel resistance in this population was approximately 33.2% (n = 70). The frequencies of CYP2C19*2 and *3 were significantly higher in non-responder than those in responders. After adjusting for established risk factors, CYP2C19*2 and *3 alleles independently increased the risk of clopidogrel resistance with adjusted ORs 2.94 (95%CI, 1.65-5.26; p<0.001) and 11.26 (95%CI, 2.47-51.41; p = 0.002, respectively). Patients with *2 or *3 allele and combined with smoking, diabetes and increased platelet count had markedly increased risk of clopidogrel resistance. No association was observed between PON1 Q192R and clopidogrel resistance (adjusted OR = 1.13, 95%CI, 0.70-1.82; p = 0.622). Significantly higher platelet aggregation values were found in CYP2C19*2 and *3 patients when compared with *1/*1 allele carriers (p = 1.98 × 10(-6)). For PON1 Q192R genotypes, aggregation values were similar across all genotype groups (p = 0.359). There was no evidence of gene-gene interaction or LD between CYP2C19 and PON1 polymorphisms on ADP-induced platelet aggregation. Our findings indicated that only CYP2C19*2 and *3 alleles had an influence on clopidogrel resistance. The risk of clopidogrel resistance increased further with smoking, diabetes, and increased platelet count.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Siriraj, Bangkoknoi, Bangkok, Thailand.
authors.forename: Damrus
authors.initials: D
authors.lastname: Tresukosol
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Siriraj Hospital, Mahidol University, Siriraj, Bangkoknoi, Bangkok, Thailand; Integrative Computation BioScience Center (ICBS), Mahidol University, Salaya, Nakhon Prathom, Thailand.
authors.forename: Bhoom
authors.initials: B
authors.lastname: Suktitipat
authors.affiliation: Department of Health Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Siriraj, Bangkoknoi, Bangkok, Thailand.
authors.forename: Saowalak
authors.initials: S
authors.lastname: Hunnangkul
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Siriraj Hospital, Mahidol University, Siriraj, Bangkoknoi, Bangkok, Thailand.
authors.forename: Ruttakarn
authors.initials: R
authors.lastname: Kamkaew
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Siriraj Hospital, Mahidol University, Siriraj, Bangkoknoi, Bangkok, Thailand.
authors.forename: Saiphon
authors.initials: S
authors.lastname: Poldee
authors.affiliation: Department of Health Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Siriraj, Bangkoknoi, Bangkok, Thailand.
authors.forename: Boonrat
authors.initials: B
authors.lastname: Tassaneetrithep
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Siriraj Hospital, Mahidol University, Siriraj, Bangkoknoi, Bangkok, Thailand.
authors.forename: Atip
authors.initials: A
authors.lastname: Likidlilid
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D043303:Aryldialkylphosphatase / Q000235:genetics*; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D010975:Platelet Aggregation Inhibitors; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D043303:Aryldialkylphosphatase; D013988:Ticlopidine