title: The CYP2C19*2 and CYP2C19*17 Polymorphisms play a Vital Role in Clopidogrel Responsiveness after Percutaneous Coronary Intervention: A Pharmacogenomics Study.
abstract: Clopidogrel inhibits platelet activation and aggregation by blocking the P2Y12receptor. Dual antiplatelet therapy with clopidogrel and aspirin is recommended treatment by current guidelines for patients undergoing percutaneous interventions. Recurrent ischaemic cardiac events after this treatment showed lack of clopidogrel responsiveness. We aimed to investigate the most noticeable variants in the genes involved in clopidogrel pharmacokinetics and pharmacodynamics. A total of 347 Turkish patients who underwent percutaneous coronary interventions with stent implantation were included in our study. Platelet reactivity (PRU) and % inhibition were measured with VerifyNow P2Y12assay in blood samples collected from patients who took a standard dose of clopidogrel (75 mg/day) for at least 7 days. The variants in the CYP2C19, CYP3A4, CYP2B6, ABCB1, ITGB3 and PON1 genes were genotyped using the Sequenom MassARRAY system. When grouped, the patients with PRU values >208 as non-responsiveness to clopidogrel therapy; 104 (30%) patients were non-responders and 243 (70%) patients were responders. A significant association was found between the CYP2C19*2 (G636A) polymorphism and non-responsiveness to clopidogrel therapy (p < 0.001). An allele frequency of this single nucleotide polymorphism was high in non-responders; its odds ratio was 2.92 compared with G allele (p < 0.001). PRU values of CT genotypes were lower (p = 0.029) and % inhibition values of CT genotypes were higher (p = 0.008) compared with CC genotypes for the CYP2C19*17 (C806T) polymorphism. None of the other genetic variants were found to be statistically associated with non-responsiveness to clopidogrel and antiplatelet activity. Our findings suggest that the CYP2C19*2 polymorphism is associated with non-responsiveness to clopidogrel therapy and the CYP2C19*17 polymorphism enhances antiplatelet activity of clopidogrel. Depending on haplotypes of these two polymorphisms, clopidogrel-treated patients can be protected or not from stent thrombosis and ischaemic events.
authors.affiliation: Department of Medical Biology and Genetics, Faculty of Medicine, Recep Tayyip Erdoğan University, Rize, Turkey.
authors.forename: Faruk
authors.initials: F
authors.lastname: Saydam
authors.affiliation: Department of Medical Biology, Faculty of Medicine, Eskişehir Osmangazi University, Eskişehir, Turkey.
authors.forename: İrfan
authors.initials: İ
authors.lastname: Değirmenci
authors.affiliation: Department of Cardiology, Faculty of Medicine, Eskişehir Osmangazi University, Eskişehir, Turkey.
authors.forename: Alparslan
authors.initials: A
authors.lastname: Birdane
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Eskişehir Osmangazi University, Eskişehir, Turkey.
authors.forename: Mahmut
authors.initials: M
authors.lastname: Özdemir
authors.affiliation: Department of Cardiology, Faculty of Medicine, Eskişehir Osmangazi University, Eskişehir, Turkey.
authors.forename: Taner
authors.initials: T
authors.lastname: Ulus
authors.affiliation: Department of Midwifery, School of Health, Kütahya Dumlupınar University, Kütahya, Turkey.
authors.forename: Cansu
authors.initials: C
authors.lastname: Özbayer
authors.affiliation: Department of Biostatistics, Faculty of Medicine, Eskişehir Osmangazi University, Eskişehir, Turkey.
authors.forename: Ertuğrul
authors.initials: E
authors.lastname: Çolak
authors.affiliation: Department of Cardiology, Faculty of Medicine, Eskişehir Osmangazi University, Eskişehir, Turkey.
authors.forename: Necmi
authors.initials: N
authors.lastname: Ata
authors.affiliation: Department of Medical Biology, Faculty of Medicine, Eskişehir Osmangazi University, Eskişehir, Turkey.
authors.forename: Hasan Veysi
authors.initials: HV
authors.lastname: Güneş
mesh_terms: D000368:Aged; D001241:Aspirin / Q000494:pharmacology / Q000627:therapeutic use; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000601:surgery*; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000209:etiology / Q000517:prevention & control*; D062645:Percutaneous Coronary Intervention / Q000009:adverse effects* / Q000295:instrumentation; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D011183:Postoperative Complications / Q000209:etiology / Q000517:prevention & control; D017422:Sequence Analysis, DNA; D015607:Stents / Q000009:adverse effects; D013927:Thrombosis / Q000209:etiology / Q000517:prevention & control*; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D014421:Turkey
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine; D001241:Aspirin