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European Journal of Clinical Pharmacology

, Volume 69, Issue 5, pp 1103–1112 | Cite as

Effect of the CYP2C19*2 and *3 genotypes, ABCB1 C3435T and PON1 Q192R alleles on the pharmacodynamics and adverse clinical events of clopidogrel in Chinese people after percutaneous coronary intervention

  • Xiao-Fang Tang
  • Jing Wang
  • Jia-Hui Zhang
  • Xian-Min Meng
  • Bo Xu
  • Shu-Bin Qiao
  • Yong-Jian Wu
  • Jue Chen
  • Yuan Wu
  • Ji-Lin Chen
  • Run-Lin Gao
  • Jin-Qing YuanEmail author
  • Yue-Jin YangEmail author
Pharmacogenetics

Abstract

Purpose

Chinese people are more frequent carriers of cytochrome P450 2C19 (CYP2C19) loss-of-function alleles than Caucasians. The effect of the ATP-binding cassette, sub-family B, member 1 (ABCB1), and paraoxonase 1 (PON1) variants on platelet reactivity and clinical outcomes of clopidogrel treatment has not yet been reported in Chinese patients after percutaneous coronary intervention. The aim of this study was to investigate the effect of the CYP2C19, ABCB1, and PON1 variants on clopidogrel pharmacodynamics and clinical outcomes in these patients.

Methods

Six hundred and seventy patients after percutaneous coronary intervention were enrolled in a single-center registry. The antiplatelet effect of clopidogrel was assessed by thromboelastography, and the CYP2C19, ABCB1, and PON1 genotypes were detected by the ligase detection reaction. Primary clinical endpoints included cardiovascular death, nonfatal myocardial infarction, target vessel revascularization, and stent thrombosis. The secondary clinical endpoints were thrombolysis in myocardial infarction bleeding. The follow-up period was 12 months.

Results

The frequency of the CYP2C19 loss-of-function alleles was relatively high (57.3 %). The risk of a low response to clopidogrel and composite ischemic events increased with the number of CYP2C19 loss-of-function alleles. However, there were not significant differences in clopidogrel pharmacodynamics and clinical outcomes across the ABCB1 and PON1 genotype groups; bleeding was not significantly different across the CYP2C19, ABCB1, and PON1 genotype groups.

Conclusions

The CYP2C19 loss-of-function alleles had a gene dose effect on the pharmacodynamics and composite ischemic events of clopidogrel in our study population. Neither the ABCB1 nor the PON1 genotype significantly influenced the antiplatelet effect and clinical outcomes of clopidogrel in these patients.

Keywords

Clopidogrel Polymorphisms CYP2C19 ABCB1 PON1 Platelet reactivity 

Notes

Acknowledgments

This work was supported by grants from the National Research Key Project of The Twelfth Five-Year Plan of Republic of China (No.2011BAI11B07) and National Natural Science Foundation of China (81170194). We are grateful to the Department of Cardiology, Cardiovascular Institute of Fuwai Hospital for its help in recruiting patients. We thank all members who contributed to the study. This article has been edited by Edanz Editing China.

Conflicts of interest

None.

Supplementary material

228_2012_1446_MOESM1_ESM.doc (140 kb)
ESM 1 (DOC 140 kb)

References

  1. 1.
    Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey WE 2nd, Fesmire FM, Hochman JS, Levin TN (2011) 2011 ACCF/AHA Focused Update Incorporated Into the ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 123(18):e426–e579PubMedCrossRefGoogle Scholar
  2. 2.
    Kushner FG, Hand M, Smith SC Jr, King SB 3rd, Anderson JL, Antman EM, Bailey SR, Bates ER, Blankenship JC, Casey DE (2009) 2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (updating the 2005 Guideline and 2007 Focused Update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 120(22):2271–2306PubMedCrossRefGoogle Scholar
  3. 3.
    Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, Chambers CE, Ellis SG, Guyton RA, Hollenberg SM (2011) 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation 124(23):e574–e651PubMedCrossRefGoogle Scholar
  4. 4.
    Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Macaya C, Bass TA, Costa MA (2007) Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 49(14):1505–1516PubMedCrossRefGoogle Scholar
  5. 5.
    Gurbel PA, Bliden KP, Samara W, Yoho JA, Hayes K, Fissha MZ, Tantry US (2005) Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study. J Am Coll Cardiol 46(10):1827–1832PubMedCrossRefGoogle Scholar
  6. 6.
    Matetzky S, Shenkman B, Guetta V, Shechter M, Bienart R, Goldenberg I, Novikov I, Pres H, Savion N, Varon D (2004) Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 109(25):3171–3175PubMedCrossRefGoogle Scholar
  7. 7.
    Taubert D, von Beckerath N, Grimberg G, Lazar A, Jung N, Goeser T, Kastrati A, Schomig A, Schomig E (2006) Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther 80(5):486–501PubMedCrossRefGoogle Scholar
  8. 8.
    Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Meneveau N, Steg PG, Ferrieres J, Danchin N, Becquemont L (2009) Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 360(4):363–375PubMedCrossRefGoogle Scholar
  9. 9.
    Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E (2009) Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 360(4):354–362PubMedCrossRefGoogle Scholar
  10. 10.
    Shuldiner AR, O’Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q (2009) Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 302(8):849–857PubMedCrossRefGoogle Scholar
  11. 11.
    Man M, Farmen M, Dumaual C, Teng CH, Moser B, Irie S, Noh GJ, Njau R, Close S, Wise S (2010) Genetic variation in metabolizing enzyme and transporter genes: comprehensive assessment in 3 major East Asian subpopulations with comparison to Caucasians and Africans. J Clin Pharmacol 50(8):929–940PubMedCrossRefGoogle Scholar
  12. 12.
    Lee JM, Park S, Shin DJ, Choi D, Shim CY, Ko YG, Kim JS, Shin ES, Chang CW, Lee JE (2009) Relation of genetic polymorphisms in the cytochrome P450 gene with clopidogrel resistance after drug-eluting stent implantation in Koreans. Am J Cardiol 104(1):46–51PubMedCrossRefGoogle Scholar
  13. 13.
    Kimura T, Morimoto T, Nakagawa Y, Tamura T, Kadota K, Yasumoto H, Nishikawa H, Hiasa Y, Muramatsu T, Meguro T (2009) Antiplatelet therapy and stent thrombosis after sirolimus-eluting stent implantation. Circulation 119(7):987–995PubMedCrossRefGoogle Scholar
  14. 14.
    Suh JW, Lee SP, Park KW, Lee HY, Kang HJ, Koo BK, Cho YS, Youn TJ, Chae IH, Choi DJ (2011) Multicenter randomized trial evaluating the efficacy of cilostazol on ischemic vascular complications after drug-eluting stent implantation for coronary heart disease: results of the CILON-T (influence of CILostazol-based triple antiplatelet therapy ON ischemic complication after drug-eluting stenT implantation) trial. J Am Coll Cardiol 57(3):280–289PubMedCrossRefGoogle Scholar
  15. 15.
    Jaitner J, Morath T, Byrne RA, Braun S, Gebhard D, Bernlochner I, Schulz S, Mehilli J, Schomig A, Koch W (2012) No association of ABCB1 C3435T genotype with clopidogrel response or risk of stent thrombosis in patients undergoing coronary stenting. Circ Cardiovasc Interv 5(1):82–88PubMedCrossRefGoogle Scholar
  16. 16.
    Luo M, Li J, Xu X, Sun X, Sheng W (2011) ABCB1 C3435T polymorphism and risk of adverse clinical events in clopidogrel treated patients: a meta-analysis. Thromb Res 129(6):754–759PubMedCrossRefGoogle Scholar
  17. 17.
    Rideg O, Komocsi A, Magyarlaki T, Tokes-Fuzesi M, Miseta A, Kovacs GL, Aradi D (2011) Impact of genetic variants on post-clopidogrel platelet reactivity in patients after elective percutaneous coronary intervention. Pharmacogenomics 12(9):1269–1280PubMedCrossRefGoogle Scholar
  18. 18.
    Bouman HJ, Schomig E, van Werkum JW, Velder J, Hackeng CM, Hirschhauser C, Waldmann C, Schmalz HG, ten Berg JM, Taubert D (2011) Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat Med 17(1):110–116PubMedCrossRefGoogle Scholar
  19. 19.
    Sibbing D, Koch W, Massberg S, Byrne RA, Mehilli J, Schulz S, Mayer K, Bernlochner I, Schomig A, Kastrati A (2011) No association of paraoxonase-1 Q192R genotypes with platelet response to clopidogrel and risk of stent thrombosis after coronary stenting. Eur Heart J 32(13):1605–1613PubMedCrossRefGoogle Scholar
  20. 20.
    Simon T, Steg PG, Becquemont L, Verstuyft C, Kotti S, Schiele F, Ferrari E, Drouet E, Grollier G, Danchin N (2011) Effect of paraoxonase-1 polymorphism on clinical outcomes in patients treated with clopidogrel after an acute myocardial infarction. Clin Pharmacol Ther 90(4):561–567PubMedCrossRefGoogle Scholar
  21. 21.
    Trenk D, Hochholzer W, Fromm MF, Zolk O, Valina CM, Stratz C, Neumann FJ (2011) Paraoxonase-1 Q192R polymorphism and antiplatelet effects of clopidogrel in patients undergoing elective coronary stent placement. Circ Cardiovasc Genet 4(4):429–436PubMedCrossRefGoogle Scholar
  22. 22.
    Hobson AR, Petley GW, Dawkins KD, Curzen N (2007) A novel fifteen minute test for assessment of individual time-dependent clotting responses to aspirin and clopidogrel using modified thrombelastography. Platelets 18(7):497–505PubMedCrossRefGoogle Scholar
  23. 23.
    Bliden KP, DiChiara J, Tantry US, Bassi AK, Chaganti SK, Gurbel PA (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):657–666PubMedCrossRefGoogle Scholar
  24. 24.
    Sawada T, Shinke T, Shite J, Honjo T, Haraguchi Y, Nishio R, Shinohara M, Toh R, Ishida T, Kawamori H (2011) Impact of cytochrome P450 2C19*2 polymorphism on intra-stent thrombus after drug-eluting stent implantation in Japanese patients receiving clopidogrel. Circ J 75(1):99–105PubMedCrossRefGoogle Scholar
  25. 25.
    Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, Steg PG, Morel MA, Mauri L, Vranckx P (2007) Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 115(17):2344–2351PubMedCrossRefGoogle Scholar
  26. 26.
    Mega JL, Close SL, Wiviott SD, Shen L, Walker JR, Simon T, Antman EM, Braunwald E, Sabatine MS (2010) 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):1312–1319PubMedCrossRefGoogle Scholar
  27. 27.
    Wallentin L, James S, Storey RF, Armstrong M, Barratt BJ, Horrow J, Husted S, Katus H, Steg PG, Shah SH (2010) Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet 376(9749):1320–1328PubMedCrossRefGoogle Scholar
  28. 28.
    Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T, Kurihara A (2010) Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos 38(1):92–99PubMedCrossRefGoogle Scholar
  29. 29.
    Goldstein JA, Ishizaki T, Chiba K, de Morais SM, Bell D, Krahn PM, Evans DA (1997) Frequencies of the defective CYP2C19 alleles responsible for the mephenytoin poor metabolizer phenotype in various Oriental, Caucasian, Saudi Arabian and American black populations. Pharmacogenetics 7(1):59–64PubMedCrossRefGoogle Scholar
  30. 30.
    Tantry US, Bliden KP, Suarez TA, Kreutz RP, Dichiara J, Gurbel PA (2010) Hypercoagulability, platelet function, inflammation and coronary artery disease acuity: results of the Thrombotic RIsk Progression (TRIP) study. Platelets 21(5):360–367PubMedCrossRefGoogle Scholar
  31. 31.
    Albert MA, Glynn RJ, Buring J, Ridker PM (2004) C-reactive protein levels among women of various ethnic groups living in the United States (from the Women’s Health Study). Am J Cardiol 93(10):1238–1242PubMedCrossRefGoogle Scholar
  32. 32.
    Park DW, Yun SC, Lee JY, Kim WJ, Kang SJ, Lee SW, Kim YH, Lee CW, Kim JJ, Park SW (2009) C-reactive protein and the risk of stent thrombosis and cardiovascular events after drug-eluting stent implantation. Circulation 120(20):1987–1995PubMedCrossRefGoogle Scholar
  33. 33.
    Sibbing D, Koch W, Gebhard D, Schuster T, Braun S, Stegherr J, Morath T, Schomig A, von Beckerath N, Kastrati A (2010) Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation 121(4):512–518PubMedCrossRefGoogle Scholar
  34. 34.
    Bhattacharyya T (2008) Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk. JAMA 299:1265–1276PubMedCrossRefGoogle Scholar
  35. 35.
    Hulot JS, Collet JP, Silvain J, Pena A, Bellemain-Appaix A, Barthelemy O, Cayla G, Beygui F, Montalescot G (2010) Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration: a systematic meta-analysis. J Am Coll Cardiol 56(2):134–143PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Xiao-Fang Tang
    • 1
  • Jing Wang
    • 1
  • Jia-Hui Zhang
    • 1
  • Xian-Min Meng
    • 2
  • Bo Xu
    • 1
  • Shu-Bin Qiao
    • 1
  • Yong-Jian Wu
    • 1
  • Jue Chen
    • 1
  • Yuan Wu
    • 1
  • Ji-Lin Chen
    • 1
  • Run-Lin Gao
    • 1
  • Jin-Qing Yuan
    • 1
    Email author
  • Yue-Jin Yang
    • 1
    Email author
  1. 1.Department of Cardiology, Fuwai Hospital and Cardiovascular Institute, National Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
  2. 2.State Key Laboratory of Cardiovascular Disease, Fuwai Hospital and Cardiovascular Institute, National Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina

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