title: Ticagrelor yields consistent dose-dependent inhibition of ADP-induced platelet aggregation in patients with atherosclerotic disease regardless of genotypic variations in P2RY12, P2RY1, and ITGB3.
abstract: The platelet P2Y(12) receptor is the target of clopidogrel therapy, which has been shown to reduce thromboembolic complications of atherosclerotic disease but has limitations in terms of variability of response and irreversibility of effect. This receptor is also a target for ticagrelor (AZD6140), the first reversibly binding oral P2Y(12) receptor antagonist that does not require metabolic activation and yields more consistent inhibition of platelet aggregation than clopidogrel therapy. Single nucleotide polymorphisms (SNPs) have been described in the gene for this receptor (P2RY12), some of which have been associated with variability in platelet reactivity. SNPs in P2RY1 and ITGB3 have also been reported by some groups to affect platelet reactivity to adenosine diphosphate (ADP). We assessed whether SNPs in these genes influenced the pharmacodynamic response to ticagrelor in patients enrolled in both the DISPERSE study (stable atherosclerotic disease) and the DISPERSE2 study (non-ST-segment elevation acute coronary syndromes). Platelet aggregation data (at baseline and 4 weeks) and DNA samples from clopidogrel-naive Caucasian patients treated with ticagrelor were available for 151 patients. Seventy four SNPs within three genes were genotyped. After adjustment for multiple comparisons, none of these SNPs were found to significantly influence inhibition of ADP-induced platelet aggregation by ticagrelor.
authors.affiliation: Cardiovascular Research Unit, University of Sheffield, Sheffield, UK. r.f.storey@sheffield.ac.uk
authors.forename: Robert F
authors.initials: RF
authors.lastname: Storey
authors.forename: S
authors.initials: S
authors.lastname: Melissa Thornton
authors.forename: Rachael
authors.initials: R
authors.lastname: Lawrance
authors.forename: Steen
authors.initials: S
authors.lastname: Husted
authors.forename: Mark
authors.initials: M
authors.lastname: Wickens
authors.forename: Håkan
authors.initials: H
authors.lastname: Emanuelsson
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Cannon
authors.forename: Stan
authors.initials: S
authors.lastname: Heptinstall
authors.forename: Martin
authors.initials: M
authors.lastname: Armstrong
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000008:administration & dosage / Q000494:pharmacology*; D019540:Area Under Curve; D050197:Atherosclerosis / Q000097:blood* / Q000188:drug therapy; D000077144:Clopidogrel; D004305:Dose-Response Relationship, Drug; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics*; D010597:Pharmacogenetics; D010974:Platelet Aggregation / Q000187:drug effects*; D020641:Polymorphism, Single Nucleotide; D018048:Receptors, Purinergic P2 / Q000235:genetics*; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D000077486:Ticagrelor; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D039661:Integrin beta3; C546382:P2RY1 protein, human; C548576:P2RY12 protein, human; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D000077486:Ticagrelor; D000241:Adenosine; D013988:Ticlopidine