European Journal of Clinical Pharmacology

, Volume 74, Issue 4, pp 423–431 | Cite as

Effect of cytochrome P450 2C19 polymorphism on adverse cardiovascular events after drug-eluting stent implantation in a large Hakka population with acute coronary syndrome receiving clopidogrel in southern China

  • Zhixiong Zhong
  • Jingyuan Hou
  • Qifeng Zhang
  • Bin Li
  • Cunren Li
  • Zhidong Liu
  • Min Yang
  • Wei Zhong
  • Xuebo He
  • Hesen Wu
  • Miaocai Zhong
  • Pingsen Zhao
Pharmacogenetics
  • 202 Downloads

Abstract

Background and objectives

The objective of this study is to evaluate the effects of cytochrome P450 2C19 (CYP2C19) polymorphism on adverse cardiovascular events (MACE) in Hakka patients with acute coronary syndrome (ACS) receiving clopidogrel who had undergone coronary drug-eluting stent placement after percutaneous coronary intervention (PCI) in southern China.

Methods

Genotyping of CYP2C19 and MACE of 934 ACS patients with PCI on clopidogrel maintenance therapy were analyzed. Patients who carried loss-of-function CYP2C19 were treated with a 150-mg maintenance dose of clopidogrel or 90 mg of ticagrelor antiplatelet therapy, and patients who were non-carriers received clopidogrel therapy daily at a maintenance dose of 75 mg and the patients were followed-up for at least 12 months. The primary efficacy endpoint was a composite of cardiovascular death, myocardial infarction, and target vessel revascularization and stroke.

Results

The allelic frequency of CYP2C19*2 and CYP2C19*3 of Hakka patients in the current study was 31.64 and 5.19%, respectively. The CYP2C19 wild-type homozygotes (*1/*1) were the most predominant among the patients (40.36%), followed by the CYP2C19*2 heterozygotes (*1/*2) (40.26%). The distribution of CYP2C19 phenotypes was divided into extensive metabolizers (EM; 40.36%), intermediate metabolizers (IM; 45.61%), and poor metabolizers (PM; 14.03%). Based on the genotype-guided antiplatelet therapy, there was no significant association between the carrier status and the clinical outcome at 1, 6, and 12 months. In addition, no significant difference in the rates of bleeding was found among the three groups. After logistic regression analysis, hypertension was the only independent predictor of cardiovascular events (relative risk, 1.501; 95% CI, 1.011 to 2.229; P = 0.044).

Conclusions

Our results shed new light on the important benefit of testing CYP2C19 polymorphisms before prescribing clopidogrel in patients treated with drug-eluting stent implantation after PCI. The testing may help to optimize pharmacotherapy effectiveness by providing individualized treatment to the Chinese population. Our findings mandate further studies aimed at initiating genome-based personalized antiplatelet therapy in a Hakka population in southern China.

Keywords

Cytochrome P450 (CYP) 2C19 Genetic polymorphism Acute coronary syndrome Drug-eluting stent implantation Clopidogrel Cardiovascular events 

Notes

Authors’ contributions

Pingsen Zhao conceived and designed the experiments; Zhixiong Zhong, Qifeng Zhang, Bin Li, Cunren Li, Zhidong Liu, Min Yang, Wei Zhong, and Xuebo He collected the clinical data and samples; Jingyuan Hou, Hesen Wu, and Miaocai Zhong performed the experiments; Pingsen Zhao, Zhixiong Zhong, and Jingyuan Hou analyzed the data and wrote the paper. All authors have read and approved the final manuscript.

Compliance with ethical standards

The study protocol was in accordance with the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Ethics Committee of Meizhou People’s Hospital (Huangtang Hospital), Meizhou Hospital Affiliated to Sun Yat-sen University. Written informed consent was obtained from all enrolled patients, and their privacy was strictly protected.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Zaiou M, El Amri H (2017) Cardiovascular pharmacogenetics: a promise for genomically-guided therapy and personalized medicine. Clin Genet 91(3):355–370.  https://doi.org/10.1111/cge.12881 CrossRefPubMedGoogle Scholar
  2. 2.
    Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Flather MD, Haffner SM, Hamm CW, Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Brennan DM, Fabry-Ribaudo L, Booth J, Topol EJ (2006) Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 354(16):1706–1717.  https://doi.org/10.1056/NEJMoa060989 CrossRefPubMedGoogle Scholar
  3. 3.
    Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS (2009) Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 360(4):354–362.  https://doi.org/10.1056/NEJMoa0809171 CrossRefPubMedGoogle Scholar
  4. 4.
    Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K, Cannon CP, Danchin N, Giusti B, Gurbel P, Horne BD, Hulot JS, Kastrati A, Montalescot G, Neumann FJ, Shen L, Sibbing D, Steg PG, Trenk D, Wiviott SD, Sabatine MS (2010) 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.  https://doi.org/10.1001/jama.2010.1543 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Goldstein JA (2001) Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br J Clin Pharmacol 52(4):349–355.  https://doi.org/10.1046/j.0306-5251.2001.01499.x CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Small DS, Farid NA, Payne CD, Weerakkody GJ, Li YG, Brandt JT, Salazar DE, Winters KJ (2008) Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. J Clin Pharmacol 48(4):475–484.  https://doi.org/10.1177/0091270008315310 CrossRefPubMedGoogle Scholar
  7. 7.
    Hulot JS, Bura A, Villard E, Azizi M, Remones V, Goyenvalle C, Aiach M, Lechat P, Gaussem P (2006) Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 108(7):2244–2247.  https://doi.org/10.1182/blood-2006-04-013052 CrossRefPubMedGoogle Scholar
  8. 8.
    Holmes DR Jr, Dehmer GJ, Kaul S, Leifer D, O'Gara PT, Stein CM (2010) ACCF/AHA clopidogrel clinical alert: approaches to the FDA “boxed warning”: a report of the American College of Cardiology Foundation Task Force on clinical expert consensus documents and the American Heart Association endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol 56(4):321–341.  https://doi.org/10.1016/j.jacc.2010.05.013 CrossRefPubMedGoogle Scholar
  9. 9.
    Osnabrugge RL, Head SJ, Zijlstra F, ten Berg JM, Hunink MG, Kappetein AP, Janssens AC (2015) A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverse clinical outcomes in clopidogrel users. Genet Med 17(1):3–11.  https://doi.org/10.1038/gim.2014.76 CrossRefPubMedGoogle Scholar
  10. 10.
    Zhang L, Yang J, Zhu X, Wang X, Peng L, Li X, Cheng P, Yin T (2015) Effect of high-dose clopidogrel according to CYP2C19*2 genotype in patients undergoing percutaneous coronary intervention—a systematic review and meta-analysis. Thromb Res 135(3):449–458.  https://doi.org/10.1016/j.thromres.2014.12.007 CrossRefPubMedGoogle Scholar
  11. 11.
    Zabalza M, Subirana I, Sala J, Lluis-Ganella C, Lucas G, Tomas M, Masia R, Marrugat J, Brugada R, Elosua R (2012) Meta-analyses of the association between cytochrome CYP2C19 loss- and gain-of-function polymorphisms and cardiovascular outcomes in patients with coronary artery disease treated with clopidogrel. Heart 98(2):100–108.  https://doi.org/10.1136/hrt.2011.227652 CrossRefPubMedGoogle Scholar
  12. 12.
    Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA (2009) Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 302(8):849–857.  https://doi.org/10.1001/jama.2009.1232 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Bergmeijer TO, Janssen PW, Schipper JC, Qaderdan K, Ishak M, Ruitenbeek RS, Asselbergs FW, van ‘t Hof AW, Dewilde WJ, Spano F, Herrman JP, Kelder JC, Postma MJ, de Boer A, Deneer VH, ten Berg JM (2014) CYP2C19 genotype-guided antiplatelet therapy in ST-segment elevation myocardial infarction patients—rationale and design of the Patient Outcome after primary PCI (POPular) Genetics study. Am Heart J 168(1):16–22 e11.  https://doi.org/10.1016/j.ahj.2014.03.006 CrossRefPubMedGoogle Scholar
  14. 14.
    Sorich MJ, Rowland A, McKinnon RA, Wiese MD (2014) CYP2C19 genotype has a greater effect on adverse cardiovascular outcomes following percutaneous coronary intervention and in Asian populations treated with clopidogrel: a meta-analysis. Circ Cardiovasc Genet 7(6):895–902.  https://doi.org/10.1161/CIRCGENETICS.114.000669 CrossRefPubMedGoogle Scholar
  15. 15.
    Man M, Farmen M, Dumaual C, Teng CH, Moser B, Irie S, Noh GJ, Njau R, Close S, Wise S, Hockett R (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):929–940.  https://doi.org/10.1177/0091270009355161 CrossRefPubMedGoogle Scholar
  16. 16.
    Wang L, McLeod HL, Weinshilboum RM (2011) Genomics and drug response. N Engl J Med 364(12):1144–1153.  https://doi.org/10.1056/NEJMra1010600 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Chan NC, Eikelboom JW, Ginsberg JS, Lauw MN, Vanassche T, Weitz JI, Hirsh J (2014) Role of phenotypic and genetic testing in managing clopidogrel therapy. Blood 124(5):689–699.  https://doi.org/10.1182/blood-2014-01-512723 CrossRefPubMedGoogle Scholar
  18. 18.
    Antman EM, Loscalzo J (2016) Precision medicine in cardiology. Nat Rev Cardiol 13(10):591–602.  https://doi.org/10.1038/nrcardio.2016.101 CrossRefPubMedGoogle Scholar
  19. 19.
    Tanguay JF, Bell AD, Ackman ML, Bauer RD, Cartier R, Chan WS, Douketis J, Roussin A, Schnell G, Verma S, Wong G, Mehta SR (2013) Focused 2012 update of the Canadian Cardiovascular Society guidelines for the use of antiplatelet therapy. Can J Cardiol 29(11):1334–1345.  https://doi.org/10.1016/j.cjca.2013.07.001 CrossRefPubMedGoogle Scholar
  20. 20.
    Xiao ZS, Goldstein JA, Xie HG, Blaisdell J, Wang W, Jiang CH, Yan FX, He N, Huang SL, ZH X, Zhou HH (1997) Differences in the incidence of the CYP2C19 polymorphism affecting the S-mephenytoin phenotype in Chinese Han and Bai populations and identification of a new rare CYP2C19 mutant allele. J Pharmacol Exp Ther 281(1):604–609PubMedGoogle Scholar
  21. 21.
    Pang YS, Wong LP, Lee TC, Mustafa AM, Mohamed Z, Lang CC (2004) Genetic polymorphism of cytochrome P450 2C19 in healthy Malaysian subjects. Br J Clin Pharmacol 58(3):332–335.  https://doi.org/10.1111/j.1365-2125.2004.02144.x CrossRefPubMedGoogle Scholar
  22. 22.
    Scott SA, Sangkuhl K, Stein CM, Hulot JS, Mega JL, Roden DM, Klein TE, Sabatine MS, Johnson JA, Shuldiner AR (2013) Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther 94(3):317–323.  https://doi.org/10.1038/clpt.2013.105 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Hicks JK, Bishop JR, Sangkuhl K, Muller DJ, Ji Y, Leckband SG, Leeder JS, Graham RL, Chiulli DL, LL A, Skaar TC, Scott SA, Stingl JC, Klein TE, Caudle KE, Gaedigk A (2015) Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clin Pharmacol Ther 98(2):127–134.  https://doi.org/10.1002/cpt.147 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Lamba JK, Dhiman RK, Kohli KK (1998) Genetic polymorphism of the hepatic cytochrome P450 2C19 in north Indian subjects. Clin Pharmacol Ther 63(4):422–427.  https://doi.org/10.1016/S0009-9236(98)90037-6 CrossRefPubMedGoogle Scholar
  25. 25.
    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):59–64.  https://doi.org/10.1097/00008571-199702000-00008 CrossRefPubMedGoogle Scholar
  26. 26.
    Herrlin K, Massele AY, Jande M, Alm C, Tybring G, Abdi YA, Wennerholm A, Johansson I, Dahl ML, Bertilsson L, Gustafsson LL (1998) Bantu Tanzanians have a decreased capacity to metabolize omeprazole and mephenytoin in relation to their CYP2C19 genotype. Clin Pharmacol Ther 64(4):391–401.  https://doi.org/10.1016/S0009-9236(98)90070-4 CrossRefPubMedGoogle Scholar
  27. 27.
    Allabi AC, Gala JL, Desager JP, Heusterspreute M, Horsmans Y (2003) Genetic polymorphisms of CYP2C9 and CYP2C19 in the Beninese and Belgian populations. Br J Clin Pharmacol 56(6):653–657.  https://doi.org/10.1046/j.1365-2125.2003.01937.x CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Kubota T, Chiba K, Ishizaki T (1996) Genotyping of S-mephenytoin 4′-hydroxylation in an extended Japanese population. Clin Pharmacol Ther 60(6):661–666.  https://doi.org/10.1016/S0009-9236(96)90214-3 CrossRefPubMedGoogle Scholar
  29. 29.
    Nakamura K, Goto F, Ray WA, McAllister CB, Jacqz E, Wilkinson GR, Branch RA (1985) Interethnic differences in genetic polymorphism of debrisoquin and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin Pharmacol Ther 38(4):402–408.  https://doi.org/10.1038/clpt.1985.194 CrossRefPubMedGoogle Scholar
  30. 30.
    Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-Brentano C, Montalescot G (2009) Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 373(9660):309–317.  https://doi.org/10.1016/S0140-6736(08)61845-0 CrossRefPubMedGoogle Scholar
  31. 31.
    Trenk D, Hochholzer W, Fromm MF, Chialda LE, Pahl A, Valina CM, Stratz C, Schmiebusch P, Bestehorn HP, Buttner HJ, Neumann FJ (2008) Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol 51(20):1925–1934.  https://doi.org/10.1016/j.jacc.2007.12.056 CrossRefPubMedGoogle Scholar
  32. 32.
    Xie X, Ma YT, Yang YN, Li XM, Ma X, ZY F, Zheng YY, Chen BD, Liu F (2013) CYP2C19 phenotype, stent thrombosis, myocardial infarction, and mortality in patients with coronary stent placement in a Chinese population. PLoS One 8(3):e59344.  https://doi.org/10.1371/journal.pone.0059344 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Sofi F, Giusti B, Marcucci R, Gori AM, Abbate R, Gensini GF (2011) Cytochrome P450 2C19*2 polymorphism and cardiovascular recurrences in patients taking clopidogrel: a meta-analysis. Pharmacogenomics J 11(3):199–206.  https://doi.org/10.1038/tpj.2010.21 CrossRefPubMedGoogle Scholar
  34. 34.
    Friede K, Li J, Voora D (2017) Use of pharmacogenetic information in the treatment of cardiovascular disease. Clin Chem 63(1):177–185.  https://doi.org/10.1373/clinchem.2016.255232 CrossRefPubMedGoogle Scholar
  35. 35.
    Depta JP, Lenzini PA, Lanfear DE, Wang TY, Spertus JA, Bach RG, Cresci S (2015) Clinical outcomes associated with proton pump inhibitor use among clopidogrel-treated patients within CYP2C19 genotype groups following acute myocardial infarction. Pharmacogenomics J 15(1):20–25.  https://doi.org/10.1038/tpj.2014.28 CrossRefPubMedGoogle Scholar
  36. 36.
    Cresci S, Depta JP, Lenzini PA, Li AY, Lanfear DE, Province MA, Spertus JA, Bach RG (2014) Cytochrome p450 gene variants, race, and mortality among clopidogrel-treated patients after acute myocardial infarction. Circ Cardiovasc Genet 7(3):277–286.  https://doi.org/10.1161/CIRCGENETICS.113.000303 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Shechter M (2003) Atorvastatin and the ability of clopidogrel to inhibit platelet aggregation. Circulation 107(22):210e–2210.  https://doi.org/10.1161/01.CIR.0000076180.03211.BD CrossRefGoogle Scholar
  38. 38.
    Malek LA, Przyluski J, Spiewak M, Klopotowski M, Kostrzewa G, Kruk M, Ploski R, Witkowski A, Ruzyllo W (2010) Cytochrome P450 2C19 polymorphism, suboptimal reperfusion and all-cause mortality in patients with acute myocardial infarction. Cardiology 117(2):81–87.  https://doi.org/10.1159/000320093 CrossRefPubMedGoogle Scholar
  39. 39.
    Sim SC, Risinger C, Dahl ML, Aklillu E, Christensen M, Bertilsson L, Ingelman-Sundberg M (2006) A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther 79(1):103–113.  https://doi.org/10.1016/j.clpt.2005.10.002 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  • Zhixiong Zhong
    • 1
  • Jingyuan Hou
    • 2
  • Qifeng Zhang
    • 1
  • Bin Li
    • 1
  • Cunren Li
    • 1
  • Zhidong Liu
    • 1
  • Min Yang
    • 1
  • Wei Zhong
    • 1
  • Xuebo He
    • 1
  • Hesen Wu
    • 2
    • 3
  • Miaocai Zhong
    • 2
    • 3
  • Pingsen Zhao
    • 2
    • 3
  1. 1.Center for Cardiovascular Diseases, Meizhou People’s Hospital (Huangtang Hospital)Meizhou Hospital Affiliated to Sun Yat-sen UniversityMeizhouPeople’s Republic of China
  2. 2.Clinical Core Laboratory, Center for Precision Medicine, Meizhou People’s Hospital (Huangtang Hospital)Meizhou Hospital Affiliated to Sun Yat-sen UniversityMeizhouPeople’s Republic of China
  3. 3.Center for Precision Medicine, Meizhou People’s Hospital (Huangtang Hospital)Meizhou Hospital Affiliated to Sun Yat-sen UniversityMeizhouPeople’s Republic of China

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