Platelets, June 2006; 17(4): 250–258 ORIGINAL ARTICLE Common sequence variations in the P2Y 12 and CYP3A5 genes do not explain the variability in the inhibitory effects of clopidogrel therapy SIMON M. G. SMITH 1 , HEATHER M. JUDGE 1 , GARY PETERS 2 , MARTIN ARMSTRONG 3 , PIERRE FONTANA 4 , PASCALE GAUSSEM 4 , MARTINA E. DALY 5 , & ROBERT F. STOREY 1 1 Cardiovascular Research Unit, University of Sheffield, Division of Clinical Sciences (North), Northern General Hospital, Sheffield, UK, 2 Astra Zeneca, Wilmington, DE, USA, 3 AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK, 4 Inserm U428, University Paris Descartes and Ho ˆpital Europe ´en Georges Pompidou, Paris, France, and 5 Academic Unit of Haematology, University of Sheffield, Division of Genomic Medicine, University of Sheffield Medical School, Sheffield, UK (Received 19 October 2005; accepted 28 October 2005) Abstract The efficacy of the platelet P2Y 12 receptor antagonist clopidogrel, which undergoes cytochrome-mediated metabolism to its active form, shows marked inter-individual variability. We investigated whether polymorphic variations in the P2Y 12 gene, which have been linked to platelet aggregation phenotypes, or the cytochrome P450 3A5 gene 6986G > A polymorphism, which largely determines CYP3A5 expression, influence the response to clopidogrel therapy. Fifty-four patients listed for elective percutaneous coronary intervention were studied using ADP-induced optical aggregometry, whole-blood single platelet counting (WBSPC) aggregometry, and flow-cytometric analysis of platelet P-selectin expression and platelet-monocyte conjugate formation. Platelet reactivity was measured at baseline, 4 h post clopidogrel 300 mg, and 10 and 28 days following clopidogrel 75 mg daily. A further 55 patients were studied using ADP-induced WBSPC at baseline and 4 h post clopidogrel 600 mg. Patients were genotyped for P2Y 12 haplotype and the CYP3A5 6986G > A single nucleotide polymorphism. Neither genotype was found to significantly influence the inhibition of platelet responses by either clopidogrel regimen. In conclusion, common sequence variations within the P2Y 12 and CYP3A5 genes do not contribute any major effect to the inter-patient variability in clopidogrel efficacy. Keywords: Clopidogrel, P2Y12, cytochrome P450 3A5, polymorphism Introduction Clopidogrel therapy has proven cardiovascular benefit in an increasing number of clinical scenarios. Clopidogrel reduces cardiovascular events in patients with stable atherosclerotic disease, patients with acute coronary syndromes whether ST-elevation myocardial infarction (STEMI) or non-STEMI, and in patients undergoing percutaneous coronary intervention (PCI) [1–4]. The anti-platelet effects of clopidogrel, however, demonstrate wide inter- individual variability [5–9] and patients with clopidogrel resistance may be at increased athero- thrombotic risk [10–13]. Clopidogrel partially and irreversibly inhibits the platelet P2Y 12 receptor via an active metabolite [14, 15] which is produced mainly through the action of hepatic cytochrome P450 3A4 and 3A5 [16]. Inter-individual expression and activity of CYP3A4 and 3A5 varies considerably, but, whilst allelic variants of the CYP3A4 gene contribute little to this variability [17], the CYP3A5 6986 G>A polymorphism largely dictates 3A5 expression, with the G allele introducing an alternative splicing site that results in a truncated protein having reduced enzymatic activity [18, 19]. Inherited variations of the platelet P2Y 12 receptor gene have been associated with differences in adenosine diphosphate (ADP)-induced platelet reactivity. The P2Y 12 H2 haplotype has been associated with increased platelet reactivity, as assessed by optical aggregometry (OA) [20], and an Correspondence: Dr Simon M. G. Smith, Clinical Research Fellow, Cardiovascular Research Unit, Clinical Sciences Centre, Northern General Hospital, Herries Road, Sheffield, South Yorkshire S5 7AU, UK. Tel: 44 114 2266084. Fax: 44 114 2619587. E-mail: s.m.g.smith@sheffield.ac.uk ISSN 0953–7104 print/ISSN 1369–1635 online ß 2006 Taylor & Francis DOI: 10.1080/09537100500475844 Platelets Downloaded from informahealthcare.com by University of Geneva on 10/12/14 For personal use only.