Skip to main content
SpringerLink
Log in

Correlation Between SNPs in Candidate Genes and VerifyNow-Detected Platelet Responsiveness to Aspirin and Clopidogrel Treatment

  • ORIGINAL ARTICLE
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Purpose

Patients with high on-treatment platelet reactivity (HPR) against aspirin or clopidogrel are at increased risk for adverse cardiovascular events. In this study, we explored the predictive value of common SNPs for the on-treatment platelet reactivity (OPR) against aspirin and clopidogrel assessed by VerifyNow assays.

Methods

This study recruited 286 Han Chinese individuals undergoing antiplatelet treatment, including 159 cases with aspirin only (100 mg/day) and 127 cases with dual therapy (aspirin 100 mg/day plus clopidogrel 75 mg/day) for at least 2 weeks. The OPR against aspirin and clopidogrel were assessed by VerifyNow Aspirin (ARU) and P2Y12 assays (PRU), respectively. Genotyping for the selected 25 SNPs within 11 genes and 2 GWAS loci was carried out by ABI multiplex SNaPshot method.

Results

The results indicated that rs4244285 (CYP2C19) and rs342293 (7q22.3) were significantly associated with PRU value (both P < 0.01). As for the OPR to aspirin, a weak statistical significance was observed in rs5445 (GNB3) (P = 0.049) and rs5758 (TBXA2R) (P = 0.045). After adjusting for the covariates including gender, age and smoking, carriers of allele A of rs4244285 remained as a strong predictor for HPR against clopidogrel.

Conclusion

The current study suggests that common SNPs may predict OPR against clopidogrel as assessed by VerifyNow P2Y12, but are less likely to respond against aspirin as assessed by VerifyNow Aspirin.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig 1

Similar content being viewed by others

References

  1. Wang TH, Bhatt DL, Topol EJ. Aspirin and clopidogrel resistance: an emerging clinical entity. Eur Heart J. 2006;27:647–54.

    Article  PubMed  Google Scholar 

  2. Lev EI, Patel RT, Maresh KJ, Guthikonda S, Granada J, DeLao T, et al. Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance. J Am Coll Cardiol. 2006;47:27–33.

    Article  CAS  PubMed  Google Scholar 

  3. Cattaneo M. Aspirin and clopidogrel: efficacy, safety, and the issue of drug resistance. Arterioscler Thromb Vasc Biol. 2004;24:1980–7.

    Article  CAS  PubMed  Google Scholar 

  4. Krasopoulos G, Brister SJ, Beattie WS, Buchanan MR. Aspirin “resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis. BMJ. 2008;336:195–8.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Snoep JD, Hovens MM, Eikenboom JC, van der Bom JG, Jukema JW, Huisman MV. Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis. Am Heart J. 2007;154:221–31.

    Article  CAS  PubMed  Google Scholar 

  6. Matetzky S, Shenkman B, Guetta V, Shechter M, Beinart R, Goldenberg I, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation. 2004;109:3171–5.

    Article  CAS  PubMed  Google Scholar 

  7. Bonello L, Camoin-Jau L, Arques S, Boyer C, Panagides D, Wittenberg O, et al. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study. J Am Coll Cardiol. 2008;51:1404–11.

    Article  CAS  PubMed  Google Scholar 

  8. Wong S, Morel-Kopp MC, Chen Q, Appleberg M, Ward CM, Lewis DR. Overcoming aspirin resistance: increased platelet inhibition with combination aspirin and clopidogrel and high dose aspirin therapy in aspirin resistant patients with peripheral vascular disease. Thromb Haemost. 2006;95:1042–3.

    CAS  PubMed  Google Scholar 

  9. Angiolillo DJ, Capranzano P, Ferreiro JL, Ueno M, Capodanno D, Dharmashankar K, et al. Impact of adjunctive cilostazol therapy on platelet function profiles in patients with and without diabetes mellitus on aspirin and clopidogrel therapy. Thromb Haemost. 2011;106:253–62.

    Article  CAS  PubMed  Google Scholar 

  10. Price MJ, Berger PB, Teirstein PS, Tanguay JF, Angiolillo DJ, Spriggs D, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the gravitas randomized trial. JAMA. 2011;305:1097–105.

    Article  CAS  PubMed  Google Scholar 

  11. Collet JP, Cuisset T, Range G, Cayla G, Elhadad S, Pouillot C, et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med. 2012;367:2100–9.

    Article  CAS  PubMed  Google Scholar 

  12. Trenk D, Stone GW, Gawaz M, Kastrati A, Angiolillo DJ, Muller U, et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the trigger-pci (testing platelet reactivity in patients undergoing elective stent placement on clopidogrel to guide alternative therapy with prasugrel) study. J Am Coll Cardiol. 2012;59:2159–64.

    Article  CAS  PubMed  Google Scholar 

  13. Aradi D, Storey RF, Komocsi A, Trenk D, Gulba D, Kiss RG, et al. Expert position paper on the role of platelet function testing in patients undergoing percutaneous coronary intervention. Eur Heart J. 2014;35:209–15.

    Article  PubMed Central  PubMed  Google Scholar 

  14. Aradi D, Collet JP, Mair J, Plebani M, Merkely B, Jaffe AS, et al. Platelet function testing in acute cardiac care - is there a role forprediction or prevention of stent thrombosis and bleeding? Thromb Haemost. 2015;113:221–30.

    Article  PubMed  Google Scholar 

  15. Campo G, Miccoli M, Tebaldi M, Marchesini J, Fileti L, Monti M, et al. Genetic determinants of on-clopidogrel high platelet reactivity. Platelets. 2011;22:399–407.

    Article  CAS  PubMed  Google Scholar 

  16. Feher G, Feher A, Pusch G, Lupkovics G, Szapary L, Papp E. The genetics of antiplatelet drug resistance. Clin Genet. 2009;75:1–18.

    Article  CAS  PubMed  Google Scholar 

  17. Li Y, Wang WJ, Cao H, Lu J, Wu C, Hu FY, et al. Genetic association of foxo1a and foxo3a with longevity trait in han chinese populations. Hum Mol Genet. 2009;18:4897–904.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Palacajornsuk P, Halter C, Isakova V, Tarnawski M, Farmar J, Reid ME, et al. Detection of blood group genes using multiplex snapshot method. Transfusion. 2009;49:740–9.

    Article  CAS  PubMed  Google Scholar 

  19. Blais N, Pharand C, Lordkipanidze M, Sia YK, Merhi Y, Diodati JG. Response to aspirin in healthy individuals. Cross-comparison of light transmission aggregometry, verifynow system, platelet count drop, thromboelastography (teg) and urinary 11-dehydrothromboxane b(2). Thromb Haemost. 2009;102:404–11.

    CAS  PubMed  Google Scholar 

  20. Nielsen HL, Kristensen SD, Thygesen SS, Mortensen J, Pedersen SB, Grove EL, et al. Aspirin response evaluated by the verifynow aspirin system and light transmission aggregometry. Thromb Res. 2008;123:267–73.

    Article  CAS  PubMed  Google Scholar 

  21. Breet NJ, van Werkum JW, Bouman HJ, Kelder JC, Harmsze AM, Hackeng CM, Ten Berg JM. High on-treatment platelet reactivity to both aspirin and clopidogrel is associated with the highest risk of adverse events following percutaneous coronary intervention. Heart. 2011;97:983–90

  22. Ko YG, Suh JW, Kim BH, Lee CJ, Kim JS, Choi D, et al. Comparison of 2 point-of-care platelet function tests, verifynow assay and multiple electrode platelet aggregometry, for predicting early clinical outcomes in patients undergoing percutaneous coronary intervention. Am Heart J. 2011;161:383–90.

    Article  PubMed  Google Scholar 

  23. Gaglia MA, Torguson R, Pakala R, Xue Z, Sardi G, Suddath WO, et al. Correlation between light transmission aggregometry, verifynow p2y12, and vasp-p platelet reactivity assays following percutaneous coronary intervention. J Interv Cardiol. 2011;24:529–34.

    Article  PubMed  Google Scholar 

  24. Madsen EH, Saw J, Kristensen SR, Schmidt EB, Pittendreigh C, Maurer-Spurej E. Long-term aspirin and clopidogrel response evaluated by light transmission aggregometry, verifynow, and thrombelastography in patients undergoing percutaneous coronary intervention. Clin Chem. 2010;56:839–47.

    Article  CAS  PubMed  Google Scholar 

  25. Kim IS, Jeong YH, Kang MK, Koh JS, Park Y, Hwang SJ, et al. Correlation of high post-treatment platelet reactivity assessed by light transmittance aggregometry and the verifynow p2y12 assay. J Thromb Thrombolysis. 2010;30:486–95.

    Article  PubMed  Google Scholar 

  26. Patti G, Pasceri V, Vizzi V, Ricottini E, Di Sciascio G. Usefulness of platelet response to clopidogrel by point-of-care testing to predict bleeding outcomes in patients undergoing percutaneous coronary intervention (from the antiplatelet therapy for reduction of myocardial damage during angioplasty-bleeding study). Am J Cardiol. 2011;107:995–1000.

    Article  PubMed  Google Scholar 

  27. Sibbing D, Stegherr J, Latz W, Koch W, Mehilli J, Dorrler K, et al. Cytochrome p450 2c19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J. 2009;30:916–22.

    Article  CAS  PubMed  Google Scholar 

  28. Jang JS, Cho KI, Jin HY, Seo JS, Yang TH, Kim DK, et al. Meta-analysis of cytochrome p450 2c19 polymorphism and risk of adverse clinical outcomes among coronary artery disease patients of different ethnic groups treated with clopidogrel. Am J Cardiol. 2012;110:502–8.

    Article  CAS  PubMed  Google Scholar 

  29. Frere C, Cuisset T, Gaborit B, Alessi MC, Hulot JS. The cyp2c19*17 allele is associated with better platelet response to clopidogrel in patients admitted for non-st acute coronary syndrome. J Thromb Haemost. 2009;7:1409–11.

    Article  CAS  PubMed  Google Scholar 

  30. Sibbing D, Koch W, Gebhard D, Schuster T, Braun S, Stegherr J, et al. Cytochrome 2c19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation. 2010;121:512–8.

    Article  CAS  PubMed  Google Scholar 

  31. Chen L, Qin S, Xie J, Tang J, Yang L, Shen W, et al. Genetic polymorphism analysis of cyp2c19 in chinese han populations from different geographic areas of mainland china. Pharmacogenomics. 2008;9:691–702.

    Article  CAS  PubMed  Google Scholar 

  32. Hulot JS, Collet JP, Silvain J, Pena A, Bellemain-Appaix A, Barthelemy O, et al. 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. 2010;56:134–43.

    Article  CAS  PubMed  Google Scholar 

  33. Gladding P, Webster M, Zeng I, Farrell H, Stewart J, Ruygrok P, et al. The pharmacogenetics and pharmacodynamics of clopidogrel response: an analysis from the princ (plavix response in coronary intervention) trial. JACC Cardiovasc Interv. 2008;1:620–7.

    Article  PubMed  Google Scholar 

  34. Soranzo N, Rendon A, Gieger C, Jones CI, Watkins NA, Menzel S, et al. A novel variant on chromosome 7q22.3 associated with mean platelet volume, counts, and function. Blood. 2009;113:3831–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Martin JF, Bath PM, Burr ML. Influence of platelet size on outcome after myocardial infarction. Lancet. 1991;338:1409–11.

    Article  CAS  PubMed  Google Scholar 

  36. Chu SG, Becker RC, Berger PB, Bhatt DL, Eikelboom JW, Konkle B, et al. Mean platelet volume as a predictor of cardiovascular risk: a systematic review and meta-analysis. J Thromb Haemost. 2010;8:148–56.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–57.

    Article  CAS  PubMed  Google Scholar 

  38. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001–15.

    Article  CAS  PubMed  Google Scholar 

  39. Postula M, Kaplon-Cieslicka A, Rosiak M, Kondracka A, Serafin A, Filipiak KJ, et al. Genetic determinants of platelet reactivity during acetylsalicylic acid therapy in diabetic patients: evaluation of 27 polymorphisms within candidate genes. J Thromb Haemost. 2011;9:2291–301.

    Article  CAS  PubMed  Google Scholar 

  40. Hobson AR, Petley G, Morton G, Dawkins KD, Curzen NP. Point-of-care platelet function assays demonstrate reduced responsiveness to clopidogrel, but not aspirin, in patients with drug-eluting stent thrombosis whilst on dual antiplatelet therapy. Thromb J. 2008;6:1.

    Article  PubMed Central  PubMed  Google Scholar 

  41. Gluckman TJ, McLean RC, Schulman SP, Kickler TS, Shapiro EP, Conte JV, et al. Effects of aspirin responsiveness and platelet reactivity on early vein graft thrombosis after coronary artery bypass graft surgery. J Am Coll Cardiol. 2011;57:1069–77.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Campo G, Fileti L, de Cesare N, Meliga E, Furgieri A, Russo F, et al. Long-term clinical outcome based on aspirin and clopidogrel responsiveness status after elective percutaneous coronary intervention: A 3t/2r (tailoring treatment with tirofiban in patients showing resistance to aspirin and/or resistance to clopidogrel) trial substudy. J Am Coll Cardiol. 2010;56:1447–55.

    Article  CAS  PubMed  Google Scholar 

  43. Frelinger 3rd AL, Li Y, Linden MD, Barnard MR, Fox ML, Christie DJ, et al. Association of cyclooxygenase-1-dependent and -independent platelet function assays with adverse clinical outcomes in aspirin-treated patients presenting for cardiac catheterization. Circulation. 2009;120:2586–96.

    Article  CAS  PubMed  Google Scholar 

  44. Bouman HJ, Schomig E, van Werkum JW, Velder J, Hackeng CM, Hirschhauser C, et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat Med. 2011;17:110–6.

    Article  CAS  PubMed  Google Scholar 

  45. Price MJ, Murray SS, Angiolillo DJ, Lillie E, Smith EN, Tisch RL, et al. Influence of genetic polymorphisms on the effect of high- and standard-dose clopidogrel after percutaneous coronary intervention: the gift (genotype information and functional testing) study. J Am Coll Cardiol. 2012;59:1928–37.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Mr. Ding Da in Genesky Biotechnologies Inc., Shanghai, China, for the expert technical support in the genotyping analysis.

Source of Funding

The study was jointly supported by a grant from the Chinese Ministry of Health, and Zhejiang Provincial Department of health, China (No. WKJ2009-2-034).

Conflict of Interests

None

Author information

Authors and Affiliations

  1. Cardiology Center, Ningbo First Hospital, Ningbo University, Ningbo, 315010, People’s Republic of China

    Hanbin Cui, Shaoyi Lin, Xiaomin Chen, Wenhui Gao, Xiaojing Li, Honglin Zhou, Weiping Du, Shenghuang Wang & Ruochi Zhao

Authors
  1. Hanbin Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shaoyi Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaomin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wenhui Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaojing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Honglin Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Weiping Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shenghuang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ruochi Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hanbin Cui.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cui, H., Lin, S., Chen, X. et al. Correlation Between SNPs in Candidate Genes and VerifyNow-Detected Platelet Responsiveness to Aspirin and Clopidogrel Treatment. Cardiovasc Drugs Ther 29, 137–146 (2015). https://doi.org/10.1007/s10557-015-6585-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10557-015-6585-6

Keywords

Search

Navigation