Skip to main content
Log in

Association between CYP2C19*2/*3 Polymorphisms and Coronary Heart Disease

  • Published:
Current Medical Science Aims and scope Submit manuscript

Abstract

This study sought to explore the relationship between cytochrome P450 2C19 (CYP2C19) *2/*3 polymorphisms and the development of coronary heart disease (CHD), and to evaluate the influence of the single nucleotide polymorphisms (SNPs) on the occurrence of adverse clinical events in CHD patients. A total of 231 consecutive patients candidate for percutaneous coronary intervention genotyped for CYP2C19*2 (681G>A) and *3 (636G>A) polymorphisms were enrolled. The adverse clinical events were recorded during a follow-up period of 14 months. The incidence of CHD, according to coronary angiography, was significantly higher (P=0.025) in CYP2C19*2 carriers group. Stepwise binary logistic regression analysis revealed that among factors that potentially influenced the presence of CHD (age>60 years, gender, BMI, etc.), CYP2C19*2 carriers (OR 1.94, 95% CI: 1.08–3.50, P=0.028) and male gender (OR 2.74, 95% CI: 1.58–4.76, P=0.001) were independent predictors, which were associated with the presence of CHD. The follow-up results showed that the incidence of adverse cardiovascular events within 14 months of discharge was significantly higher in the CYP2C19*2 carriers than in the non-carriers (21.6% vs. 6.3%, P=0.019). The results of the multivariate Cox proportional hazards model showed that CYP2C19*2 loss-of-function was the only independent factor which predicted the coronary events during the follow-up period of 14 months (OR=3.65, 95% CI 1.09–12.25, P=0.036). The adverse impact of CYP2C19*2 polymorphisms was found not only in the risk of the presence of CHD, but also in the adverse cardiovascular events in CHD patients during the follow-up period of 14 months. However the same influence was not found in CYP2C19*3 mutation in Chinese Han population.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Roman RJ. P–450 metabolites of arachidonic acid in the control of cardiovascular function. J Physiol Rev, 2002, 82(1):131–185

    Article  CAS  Google Scholar 

  2. Oyekan AO, McAward K, Conetta J, et al. Endothelin–1 and CYP450 arachidonate metabolites interact to promote tissue injury in DOCA–salt hypertension. Am J Physiol, 1999,276(3):R766–R775

    Google Scholar 

  3. Wu S, Moomaw CR, Tomer KB, et al. Molecular cloning and expression of CYP2J2, a human cytochrome P450 arachidonic acid epoxygenase highly expressed in heart. J Biol Chem, 1996,271(7):3460–3468

    Article  CAS  PubMed  Google Scholar 

  4. Lin JHC, Kobari Y, Zhu Y, et al. Human umbilical vein endothelial cells express P450 2C8 mRNA: cloning of endothelial P450 epoxygenase. Endothelium, 1996,4(3):219–229

    Article  CAS  Google Scholar 

  5. Ingelman–Sundberg M, Sim SC, Gomez A, et al. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther, 2007,116(3):496–526

    Article  CAS  PubMed  Google Scholar 

  6. Ercan B, Ayaz L, Cicek D, et al. Role of CYP2C9 and CYP2C19 polymorphisms in patients with atherosclerosis. Cell Biochem Funct, 2008,26(3):309–313

    Article  CAS  PubMed  Google Scholar 

  7. Yang YN, Wang XL, Ma YT, et al. Association of interaction between smoking and CYP 2C19*3 polymorphism with coronary artery disease in a Uighur population. Clin Appl Thromb Hemost, 2010,16(5):579–583

    Article  CAS  PubMed  Google Scholar 

  8. Fichtlscherer S, Dimmeler S, Breuer S, et al. Inhibition of cytochrome P450 2C9 improves endotheliumdependent, nitric oxide–mediated vasodilatation in patients with coronary artery disease. Circulation, 2004,109(2):178–183

    Article  CAS  PubMed  Google Scholar 

  9. Shin DJ, Kwon J, Park AR, et al. Association of CYP2C19*2 and *3 genetic variants with essential hypertension in Koreans. Yonsei Med J, 2012,53(6):1113–1119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gasparyan AY, Watson T, Lip GY. The Role of Aspirin in Cardiovascular Prevention Implications of Aspirin Resistance. J Am Coll Cardiol, 2008,51(19):1829–1843

    Article  CAS  PubMed  Google Scholar 

  11. Holmes DR, Dehmer GJ, Kaul S, et al. 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, 2010,56(4):321–341

    Article  CAS  PubMed  Google Scholar 

  12. Savi P, Pereillo JM, Uzabiaga MF, et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost, 2000,84(5):891–896

    Article  CAS  PubMed  Google Scholar 

  13. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p–450 polymorphisms and response to clopidogrel. N Engl J Med, 2009,360(4):354–362

    Article  CAS  PubMed  Google Scholar 

  14. Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet, 2009,373(9660):309–317

    Article  CAS  PubMed  Google Scholar 

  15. Shuldiner AR, O’Connell JR, Bliden KP, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA, 2009,302(8):849–857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Simon T, Verstuyft C, Mary–Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med, 2009,360(4):363–375

    Article  CAS  PubMed  Google Scholar 

  17. Food U, Drug Administration. FDA Drug Safety Communication: Reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug. Drug Safety and Availability. Food and Drug Administration (United States), 2010

    Google Scholar 

  18. Mega JL, Simon Y, Collet JP, et al. Reduced–function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta–analysis. JAMA, 2010,304(16):1821–1830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pare G, Mehta SR, Yusuf S, et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med, 2010,363(18):1704–1714

    Article  CAS  PubMed  Google Scholar 

  20. Holmes MV, Perel P, Shah T, et al. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events. JAMA, 2011,306(24):2704–2714

    Article  CAS  PubMed  Google Scholar 

  21. Desta Z, Zhao X, Shin JG, et al. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet, 2002,41(12):913–958

    Article  CAS  PubMed  Google Scholar 

  22. Man M, Farmen M, Dumaual C, et al. 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, 2010,50(8):929–940

    Article  CAS  PubMed  Google Scholar 

  23. Hunter AL, Cruz RP, Cheyne BM, et al. Cytochrome p450 enzymes and cardiovascular disease. Can J Physiol Pharmacol, 2004,82(12):1053–1060

    Article  CAS  PubMed  Google Scholar 

  24. Kazui M, Nishiya Y, Ishizuka T, et al. 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, 2010,38(1):92–99

    Article  CAS  PubMed  Google Scholar 

  25. Angiolillo DJ, Fernández–Ortiz A, Bernardo E, et al. High clopidogrel loading dose during coronary stenting: effects on drug response and interindividual variability. Eur Heart J, 2004,25(21):1903–1910

    Article  CAS  PubMed  Google Scholar 

  26. Brandt JT, Close SL, Iturria SJ, et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost, 2007,5(12):2429–2436

    Article  CAS  PubMed  Google Scholar 

  27. Umemura K, Furuta T, Kondo K. The common gene variants of CYP2C19 affect pharmacokinetics and pharmacodynamics in an active metabolite of clopidogrel in healthy subjects. J Thromb Haemostasis, 2008,6(8):1439–1441

    Article  CAS  Google Scholar 

  28. Hulot JS, Bura A, Villard E, et al. Cytochrome P450 2C19 loss–of–function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood, 2006,108(7):2244–2247

    Article  CAS  PubMed  Google Scholar 

  29. Giusti B, Gori AM, Marcucci R, et al. Cytochrome P450 2C19 loss–of–function polymorphism, but not CYP3A4 IVS10+ 12G/A and P2Y12 T744C polymorphisms, is associated with response variability to dual antiplatelet treatment in high–risk vascular patients. Pharmacogenet Genomics, 2007,17(12):1057–1064

    Article  CAS  PubMed  Google Scholar 

  30. Trenk D, Hochholzer W, Fromm MF, et al. Cytochrome P450 2C19 681G>A polymorphism and high onclopidogrel 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, 2008,51(20):1925–1934

    Article  CAS  PubMed  Google Scholar 

  31. Frere C, Cuisset T, Morange PE, et al. Effect of Cytochrome P450 Polymorphisms on Platelet Reactivity After Treatment With Clopidogrel in Acute Coronary Syndrome. Am J Cardiol, 2008,101(8):1088–1093

    Article  CAS  PubMed  Google Scholar 

  32. Wallentin L, James S, Storey RF, et al. 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, 2010,376(9749):1320–1328

    Article  CAS  PubMed  Google Scholar 

  33. Paré G, Mehta SR, Yusuf S, et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. New Engl J Med, 2010,363(18):1704–1714

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yu-ming Li.

Additional information

This work was supported by the National Natural Science Foundation of China (No. 81170238 and No. 81070121), Tianjin Municipal Science and Technology Committee (No. 09ZCZDSF04200 and No. 11JCYBJC12000) and Tianjin Chest Hospital Found 2018 (No. 2018XKZ01).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Yy., Zhou, X., Ji, Wj. et al. Association between CYP2C19*2/*3 Polymorphisms and Coronary Heart Disease. CURR MED SCI 39, 44–51 (2019). https://doi.org/10.1007/s11596-019-1998-2

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11596-019-1998-2

Key words

Navigation