Association between P2RY12 gene polymorphisms and adverse clinical events in coronary artery disease patients treated with clopidogrel: A systematic review and meta-analysis.

OBJECTIVE: Investigate the association between P2Y12 Purinoceptor (P2RY12) polymorphisms and adverse clinical events in coronary artery disease (CAD) patients treated with clopidogrel. METHODS: We performed a comprehensive database search, with a particular focus on P2RY12 polymorphisms and their effects on clopidogrel-treated CAD patients, in the PubMed, EMBASE, Cochrane Library, clinicaltrials.gov, Web of Science, and Chinese databases from their inceptions to April 8, 2017. The primary endpoints were composite ischemic events (including cardiovascular and cerebrovascular ischemic events), the secondary endpoints were independent cardiovascular events (mortality, non-fatal myocardial infarction, stent thrombosis, unstable angina, and target vessel revascularization) and the safety endpoints were bleeding events. RESULTS: Overall 10 studies and 10,810 clopidogrel-treated CAD patients were studied in the present work. Subjects of the common alleles of P2RY12 polymorphisms showed higher risk for composite ischemic events compared to non-carriers (n = 434 of 3268[13.3%] vs. n = 646 of 6133[10.5%]; RR: 1.39, 95%CI: 1.14-1.69; p = 0.001). These allele carriers also showed increased risk for stent thrombosis (RR: 2.67, 95%CI: 1.03-6.91; p = 0.04), myocardial infarction (RR: 1.60, 95%CI: 1.06-2.42; p = 0.03), and unstable angina (RR: 1.72, 95%CI: 1.37-2.16; p < 0.00001) (vs. non-carriers). There was no significant difference between two groups in terms of mortality risk, target vessel revascularization or bleeding (p = 0.29; p = 0.48, respectively). CONCLUSIONS: P2RY12 gene polymorphisms might associate with higher risk of composite ischemic events, stent thrombosis, non-fatal myocardial infarction, unstable angina. While we found no significant effect on mortality, target vessel revascularization or bleeding.

Genetic mutations in PEAR1 associated with cardiovascular outcomes in Chinese patients with acute coronary syndrome.

OBJECTIVE: To investigate the association between PEAR1 (platelet endothelial aggregation receptor-1) polymorphisms and cardiovascular outcomes in acute coronary syndrome (ACS) in patients treated with aspirin and clopidogrel. METHODS: We genotyped eight common PEAR1 SNPs (rs2768759, rs12566888, rs12041331, rs11264579, rs2644592, rs822441, rs822442, and rs4661012), also CYP2C19*2 (rs4244285) and CYP2C19*3 (rs4986893) in 196 Chinese patients with ACS. We assessed the association between PEAR1 polymorphisms and platelet inhibition rate (PIR) measured by thromboelastography (TEG). The ischemic events over 12 months were recorded, and the relationship between PEAR1 polymorphisms and ischemic events was analyzed. RESULTS: Genetic mutations in rs822441, rs822442, and CYP2C19⁎2/⁎3 alleles were significantly associated with a decrease in PIR induced by adenosine diphosphate (ADP). Carriers of the T allele in rs11264579 were less likely to have ischemic events compared with non-carriers (HR: 0.53, 95% CI: 0.30-0.94, P = .031). By contrast, carriers of the A allele in rs822442 had increased risk of ischemic events (HR: 1.82, 95% CI: 1.02-3.24, P = .043). However, these significant associations disappeared after controlling family-wise error rate. CONCLUSIONS: For Chinese patients with ACS treated with aspirin and clopidogrel, genetic mutations in rs822441/rs822442 in PEAR1 correlated significantly with platelet activity after adjusting for CYP2C19 *2/*3 alleles. The rs11264579 T allele might be a protective factor for ischemic events; rs11264579, rs822441, and rs822442 might be genetic markers worthy of further research.

Haplotype of platelet receptor P2RY12 gene is associated with residual clopidogrel on-treatment platelet reactivity.

OBJECTIVE: To investigate a possible association between common variations of the P2RY12 and the residual clopidogrel on-treatment platelet reactivity after adjusting for the influence of CYP2C19 tested by thromboelastography (TEG). METHODS: One hundred and eighty patients with acute coronary syndrome (ACS) treated with clopidogrel and aspirin were included and platelet function was assessed by TEG. Five selected P2RY12 single nucleotide polymorphisms (SNPs; rs6798347, rs6787801, rs6801273, rs6785930, and rs2046934), which cover the common variations in the P2RY12 gene and its regulatory regions, and three CYP2C19 SNPs (*2,*3,*17) were genotyped and possible haplotypes were analyzed. RESULTS: The high on-treatment platelet reactivity (HTPR) prevalence defined by a platelet inhibition rate <30% by TEG in adenosine diphosphate (ADP)-channel was 69 (38.33%). Six common haplotypes were inferred from four of the selected P2RY12 SNPs (denoted H0 to H5) according to the linkage disequilibrium R square (except for rs2046934). Haplotype H1 showed a significantly lower incidence of HTPR than the reference haplotype (H0) in the total study population while haplotypes H1 and H2 showed significantly lower incidences of HTPR than H0 in the nonsmoker subgroup after adjusting for CYP2C19 effects and demographic characteristics. rs2046934 (T744C) did not show any significant association with HTPR. CONCLUSIONS: The combination of common P2RY12 variations including regulatory regions rather than rs2046934 (T744C) that related to pharmacodynamics of clopidogrel in patients with ACS was independently associated with residual on-clopidogrel platelet reactivity. This is apart from the established association of the CYP2C19. This association seemed more important in the subgroup defined by smoking.