Similar articles

Abstract: 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.

P2RY12基因单倍体分型对急性冠脉综合征患者氯吡格雷用药后血小板反应性的影响

[1]Angiolillo, D.J., Fernandez-Ortiz, A., Bernardo, E., et al., 2005. Lack of association between the P2Y₁₂ receptor gene polymorphism and platelet response to clopidogrel in patients with coronary artery disease. Thromb. Res., 116(6):491-497.

[2]Angiolillo, D.J., Fernandez-Ortiz, A., Bernardo, E., et al., 2007. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J. Am. Coll. Cardiol., 49(14):1505-1516.

[3]Beinart, S.C., Kolm, P., Veledar, E., et al., 2005. Long-term cost effectiveness of early and sustained dual oral antiplatelet therapy with clopidogrel given for up to one year after percutaneous coronary intervention: results from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. J. Am. Coll. Cardiol., 46(5):761-769.

[4]Bierend, A., Rau, T., Maas, R., et al., 2008. P2Y₁₂ polymorphisms and antiplatelet effects of aspirin in patients with coronary artery disease. Br. J. Clin. Pharmacol., 65(4):540-547.

[5]Bliden, K.P., DiChiara, J., Tantry, U.S., et al., 2007. Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate? J. Am. Coll. Cardiol., 49(6):657-666.

[6]Bliden, K.P., Dichiara, J., Lawal, L., et al., 2008. The association of cigarette smoking with enhanced platelet inhibition by clopidogrel. J. Am. Coll. Cardiol., 52(7):531-533.

[7]Bonello, L., Bonello-Palot, N., Armero, S., et al., 2010. Impact of P2Y12-ADP receptor polymorphism on the efficacy of clopidogrel dose-adjustment according to platelet reactivity monitoring in coronary artery disease patients. Thromb. Res., 125(4):e167-e170.

[8]Cavallari, U., Trabetti, E., Malerba, G., et al., 2007. Gene sequence variations of the platelet P2Y₁₂ receptor are associated with coronary artery disease. BMC Med. Genet., 8:59.

[9]Chen, Y., Huang, X., Tang, Y., et al., 2014. GW25-e3303 Both PON1 Q192R and CYP2C19*2 influence platelet response to clopidogrel and ischemic events in Chinese patients undergoing percutaneous coronary intervention. J. Am. Coll. Cardiol., 64(16):C203.

[10]Cicko, S., Lucattelli, M., Müller, T., et al., 2010. Purinergic receptor inhibition prevents the development of smoke-induced lung injury and emphysema. J. Immunol., 185(1):688-697.

[11]Cuisset, T., Frere, C., Quilici, J., et al., 2007. Role of the T744C polymorphism of the P2Y12 gene on platelet response to a 600-mg loading dose of clopidogrel in 597 patients with non-ST-segment elevation acute coronary syndrome. Thromb. Res., 120(6):893-899.

[12]Emergency Medical Branch of Chinese Medical Doctor Association, Cardiovascular Epidemiology Branch of Chinese Medical Association, Laboratory Medicine Brance of Chinese Medical Association, 2016. Emergency rapid diagnosis and treatment of guidelines acute coronary syndrome. Chin. J. Emerg. Med., 25(4):397-404 (in Chinese).

[13]Fontana, P., Gaussem, P., Aiach, M., et al., 2003. P2Y₁₂ H2 haplotype is associated with peripheral arterial disease: a case-control study. Circulation, 108(24):2971-2973.

[14]Gremmel, T., Steiner, S., Seidinger, D., et al., 2009. Smoking promotes clopidogrel-mediated platelet inhibition in patients receiving dual antiplatelet therapy. Thromb. Res., 124(5):588-591.

[15]Gurbel, P.A., Bliden, K.P., Logan, D.K., et al., 2013. The influence of smoking status on the pharmacokinetics and pharmacodynamics of clopidogrel and prasugrel: the PARADOX study. J. Am. Coll. Cardiol., 62(6):505-512.

[16]Hochholzer, W., Trenk, D., Mega, J.L., et al., 2011. Impact of smoking on antiplatelet effect of clopidogrel and prasugrel after loading dose and on maintenance therapy. Am. Heart J., 162(3):518-526.e5.

[17]Jana, U., Ludek, S., Jana, K., et al., 2014. Genetic polymorphisms of platelet receptors in patients with acute myocardial infarction and resistance to antiplatelet therapy. Genet. Test. Mol. Biomarkers, 18(9):599-604.

[18]Jang, M.J., Jeon, Y.J., Min, K.T., et al., 2012. Polymorphisms of platelet ADP receptor P2RY12 in the risk of venous thromboembolism in the Korean population. Clin. Appl. Thromb Hemost., 18(4):416-420.

[19]Jeong, Y.H., Cho, J.H., Kang, M.K., et al., 2010. Smoking at least 10 cigarettes per day increases platelet inhibition by clopidogrel in patients with ST-segment-elevation myocardial infarction. Thromb. Res., 126(4):e334-e338.

[20]Kar, R., Meena, A., Yadav, B.K., et al., 2013. Clopidogrel resistance in North Indian patients of coronary artery disease and lack of its association with platelet ADP receptors P2Y₁ and P2Y₁₂ gene polymorphisms. Platelets, 24(4):297-302.

[21]Kim, K.A., Song, W.G., Lee, H.M., et al., 2013. Effect of P2Y₁ and P2Y₁₂ genetic polymorphisms on the ADP-induced platelet aggregation in a Korean population. Thromb Res., 132(2):221-226.

[22]Kim, Y.G., Suh, J.W., Kang, S.H., et al., 2016. Cigarette smoking does not enhance clopidogrel responsiveness after adjusting VerifyNow P2Y12 reaction unit for the influence of hemoglobin level. JACC Cardiovasc. Interv., 9(16):1680-1690.

[23]Lev, E.I., Patel, R.T., Guthikonda, S., et al., 2007. Genetic polymorphisms of the platelet receptors P2Y₁₂, P2Y₁ and GP IIIa and response to aspirin and clopidogrel. Thromb. Res., 119(3):355-360.

[24]Levine, G.N., Bates, E.R., Bittl, J.A., et al., 2016. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines: An Update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery, 2012 ACC/AHA/ACP/ AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease, 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction, 2014 AHA/ACC Guideline for the Management of Patients With Non– ST-Elevation Acute Coronary Syndromes, and 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery. Circulation, 134(10):e123-e155.

[25]Li, X.Q., Ma, N., Li, X.G., et al., 2016. Association of PON1, P2Y12 and COX1 with recurrent ischemic events in patients with extracranial or intracranial stenting. PLoS ONE, 11(2):e0148891.

[26]Liu, J., Nie, X.Y., Zhang, Y., et al., 2015. CYP2C19*2 and other allelic variants affecting platelet response to clopidogrel tested by thrombelastography in patients with acute coronary syndrome. Chin. Med. J. (Engl.), 128(16): 2183-2188.

[27]Malek, L.A., Kisiel, B., Spiewak, M., et al., 2008. Coexisting polymorphisms of P2Y12 and CYP2C19 genes as a risk factor for persistent platelet activation with clopidogrel. Circ. J., 72(7):1165-1169.

[28]Mega, J.L., Close, S.L., Wiviott, S.D., et al., 2010a. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet, 376(9749):1312-1319.

[29]Mega, J.L., Simon, T., Collet, J.P., et al., 2010b. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA, 304(16):1821-1830.

[30]Namazi, S., Kojuri, J., Khalili, A., et al., 2012. The impact of genetic polymorphisms of P2Y12, CYP3A5 and CYP2C19 on clopidogrel response variability in Iranian patients. Biochem. Pharmacol., 83(7):903-908.

[31]Oestreich, J.H., Steinhubl, S.R., Ferraris, S.P., et al., 2014. Effect of genetic variation in P2Y₁₂ on TRAP-stimulated platelet response in healthy subjects. J. Thromb. Thrombolysis, 38(3):372-379.

[32]Patti, G., Polacco, M., Taurino, E., et al., 2016. Effects of cigarette smoking on platelet reactivity during P2Y12 inhibition in patients with myocardial infarction undergoing drug-eluting stent implantation: results from the prospective cigarette smoking on platelet reactivity (COPTER) study. J. Thromb. Thrombolysis, 41(4):648-653.

[33]Peng, L., Zhang, L., Yang, J., et al., 2015. Joint effects of CYP2C19*2 and smoking status on clopidogrel responsiveness in patients with acute coronary syndrome. Int. J. Cardiol., 180(1):196-198.

[34]Price, M.J., Nayak, K.R., Barker, C.M., et al., 2009. Predictors of heightened platelet reactivity despite dual-antiplatelet therapy in patients undergoing percutaneous coronary intervention. Am. J. Cardiol., 103(10):1339-1343.

[35]Rudež, G., Pons, D., Leebeek, F., et al., 2008. Platelet receptor P2RY12 haplotypes predict restenosis after percutaneous coronary interventions. Hum. Mutat., 29(3):375-380.

[36]Rudež, G., Bouman, H.J., van Werkum, J.W., et al., 2009. Common variation in the platelet receptor P2RY12 gene is associated with residual on-clopidogrel platelet reactivity in patients undergoing elective percutaneous coronary interventions. Circ. Cardiovasc. Genet., 2(5):515-521.

[37]SIGN, 2016. SIGN 148 Acute Coronary Syndrome. Scottish Intercollegiate Guidelines Network (SIGN), Edinburgh. http://www.sign.ac.uk [June 15, 2016].

[38]Section of Interventional Cardiology of Chinese Society of Cardiology of Chinese Medical Association, Specialty Committee on Prevention and Treatment of Thrombosis of Chinese College of Cardiovascular Physicians, Editorial Board of Chinese Journal of Cardiology, 2016. Chinese guideline for percutaneous coronary intervention (2016). Chin. J. Cardiol., 44(5):382-400 (in Chinese).

[39]Shalia, K.K., Shah, V.K., Pawar, P., et al., 2013. Polymorphisms of MDR1, CYP2C19 and P2Y₁₂ genes in Indian population: effects on clopidogrel response. Indian Heart J., 65(2):158-167.

[40]Shanker, G., Kontos, J.L., Eckman, D.M., et al., 2006. Nicotine upregulates the expression of P2Y12 on vascular cells and megakaryoblasts. J. Thromb. Thrombolysis, 22(3):213-220.

[41]Sibbing, D., Bernlochner, I., Schulz, S., et al., 2012. The impact of smoking on the antiplatelet action of clopidogrel in non-ST-elevation myocardial infarction patients: results from the ISAR-REACT 4 platelet substudy. J. Thromb. Haemost., 10(10):2199-2202.

[42]Simon, T., Bhatt, D.L., Bergougnan, L., et al., 2011. Genetic polymorphisms and the impact of a higher clopidogrel dose regimen on active metabolite exposure and antiplatelet response in healthy subjects. Clin. Pharmacol. Ther., 90(2):287-295.

[43]Smith, S.M., Judge, H.M., Peters, G., et al., 2006. Common sequence variations in the P2Y₁₂ and CYP3A5 genes do not explain the variability in the inhibitory effects of clopidogrel therapy. Platelets, 17(4):250-258.

[44]Staritz, P., Kurz, K., Stoll, M., et al., 2009. Platelet reactivity and clopidogrel resistance are associated with the H2 haplotype of the P2Y₁₂-ADP receptor gene. Int. J. Cardiol., 133(3):341-345.

[45]Tang, X.F., Han, Y.L., Zhang, J.H., et al., 2015. Comparing of light transmittance aggregometry and modified thrombelastograph in predicting clinical outcomes in Chinese patients undergoing coronary stenting with clopidogrel. Chin. Med. J. (Engl.), 128(6):774-779.

[46]Tantcheva-Poór, I., Zaigler, M., Rietbrock, S., et al., 1999. Estimation of cytochrome P-450 CYP1A2 activity in 863 healthy Caucasians using a saliva-based caffeine test. Pharmacogenetics, 9(2):131-144.

[47]Ueno, M., Ferreiro, J.L., Desai, B., et al., 2012. Cigarette smoking is associated with a dose-response effect in clopidogrel-treated patients with diabetes mellitus and coronary artery disease: results of a pharmacodynamic study. JACC Cardiovasc. Interv., 5(3):293-300.

[48]Yousef, A.M., Arafat, T., Bulatova, N.R., et al., 2008. Smoking behaviour modulates pharmacokinetics of orally administered clopidogrel. J. Clin. Pharm. Ther., 33(4):439-449.

[49]Yusuf, S., Zhao, F., Mehta, S.R., et al., 2001. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N. Engl. J. Med., 345(7):494-502.

[50]Zee, R.Y., Michaud, S.E., Diehl, K.A., et al., 2008. Purinergic receptor P2Y, G-protein coupled, 12 gene variants and risk of incident ischemic stroke, myocardial infarction, and venous thromboembolism. Atherosclerosis, 197(2):694-699.

[51]Zhang, J.H., Wang, J., Tang, X.F., et al., 2016. Effect of platelet receptor gene polymorphisms on outcomes in ST-elevation myocardial infarction patients after percutaneous coronary intervention. Platelets, 27(1):75-79.

[52]Zoheir, N., Abd Elhamid, S., Abulata, N., et al., 2013. P2Y12 receptor gene polymorphism and antiplatelet effect of clopidogrel in patients with coronary artery disease after coronary stenting. Blood Coagul. Fibrinolysis, 24(5):525-531.