title: Influence of P2Y12 polymorphisms on platelet activity but not ex-vivo antiplatelet effect of ticagrelor in healthy Chinese male subjects.
abstract: Activation of platelet implicated a series of signal conduction including outside-in and inside-out related receptor-mediated signaling pathways. Ticagrelor is the first reversible P2Y12 receptor antagonist that exhibits rapid antiplatelet effect. Given that platelet aggregation varies among individuals, genetic polymorphisms in P2Y12 and subsequent signal molecular such as the G-protein beta 3 subunit (GNB3) are supposed to influence the antiplatelet effect of ticagrelor. The aim of this study was to determine whether genetic polymorphisms in P2Y12 and GNB3 genes influence ex-vivo antiplatelet activity of ticagrelor in healthy Chinese subjects. A total of 196 healthy Chinese male individuals were recruited. ADP-induced platelet aggregation was determined by using light transmittance aggregometry at baseline and after incubation of the platelet-rich plasma with 15 and 50 μmol/l ticagrelor, respectively. Nine single-nucleotide polymorphisms (SNPs) in P2Y12 and the GNB3 rs5443 polymorphism were genotyped by PCR-direct sequencing. P2Y12 haplotypes were inferred. Baseline platelet aggregation was increased in carriers of the common alleles of P2Y12 SNPs (rs1907637, rs2046934, and rs6809699) and rs6787801 TC heterozygotes (P < 0.05 for all). Results of the haplotype analyses were consistent with those of the single SNPs. Ticagrelor at both concentrations of 15 and 50 μmol/l decreased ADP-induced platelet aggregation significantly (P < 0.05, respectively). Neither single SNPs nor haplotypes of P2Y12 affected ticagrelor-induced ex-vivo inhibition of platelet aggregation. P2Y12 and GNB3 polymorphisms have no effect on the ex-vivo antiplatelet activity of ticagrelor in healthy Chinese male subjects.
authors.affiliation: aDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University bInstitute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha cCooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang dDepartment of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China.
authors.forename: Mu-Peng
authors.initials: MP
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.forename: Zhi-Peng
authors.initials: ZP
authors.lastname: Wen
authors.forename: Yan-Jiao
authors.initials: YJ
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Hong-Hao
authors.initials: HH
authors.lastname: Zhou
authors.forename: Zan-Ling
authors.initials: ZL
authors.lastname: Zhang
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Chen
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000483:Alleles; D044466:Asian People; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004336:Drug Antagonism; D005838:Genotype; D064368:Healthy Volunteers; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D015539:Platelet Activation / Q000187:drug effects / Q000235:genetics; D010974:Platelet Aggregation / Q000187:drug effects / Q000235:genetics; D053657:Platelet-Rich Plasma / Q000737:chemistry; D020641:Polymorphism, Single Nucleotide; D061251:Primary Cell Culture; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology*; D058925:Receptors, Purinergic P2Y12 / Q000235:genetics*; D017422:Sequence Analysis, DNA; D000077486:Ticagrelor
chemical_list: C000595803:GNB3 protein, human; C548576:P2RY12 protein, human; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000244:Adenosine Diphosphate; D020962:Heterotrimeric GTP-Binding Proteins; D000077486:Ticagrelor; D000241:Adenosine