title: Common sequence variations in the P2Y12 and CYP3A5 genes do not explain the variability in the inhibitory effects of clopidogrel therapy.
abstract: The efficacy of the platelet P2Y12 receptor antagonist clopidogrel, which undergoes cytochrome-mediated metabolism to its active form, shows marked inter-individual variability. We investigated whether polymorphic variations in the P2Y12 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 P2Y12 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 P2Y12 and CYP3A5 genes do not contribute any major effect to the inter-patient variability in clopidogrel efficacy.
authors.affiliation: Cardiovascular Research Unit, University of Sheffield, Division of Clinical Sciences (North), Northern General Hospital, Sheffield, UK. s.m.g.smith@sheffield.ac.uk
authors.forename: Simon M G
authors.initials: SM
authors.lastname: Smith
authors.forename: Heather M
authors.initials: HM
authors.lastname: Judge
authors.forename: Gary
authors.initials: G
authors.lastname: Peters
authors.forename: Martin
authors.initials: M
authors.lastname: Armstrong
authors.forename: Pierre
authors.initials: P
authors.lastname: Fontana
authors.forename: Pascale
authors.initials: P
authors.lastname: Gaussem
authors.forename: Martina E
authors.initials: ME
authors.lastname: Daly
authors.forename: Robert F
authors.initials: RF
authors.lastname: Storey
mesh_terms: D000077144:Clopidogrel; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D015588:Observer Variation; D010974:Platelet Aggregation / Q000187:drug effects / Q000235:genetics*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D010979:Platelet Function Tests; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011446:Prospective Studies; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2 / Q000235:genetics*; D058925:Receptors, Purinergic P2Y12; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D003577:Cytochrome P-450 Enzyme System; D000077144:Clopidogrel; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D013988:Ticlopidine