Clopidogrel Pharmacogenetics in Iranian Patients Undergoing Percutaneous Coronary Intervention
Clopidogrel is used in patients with coronary syndromes and at risk of thrombotic events or receiving percutaneous coronary intervention (PCI) for reducing heart attack and stroke. Here we present genotype and phenotype study of Iranian patients undergoing PCI treated with clopidogrel during a 6-month period of follow-up; common variants of CYP2C19, CYP3A5, CYP3A4, and ABCB1 genes were determined as well as the patients’ cardiovascular outcomes to find out the effect of these variants individually and in combination. 388 individuals receiving PCI were enrolled in this study. Different pretreatment doses of clopidogrel were prescribed under the interventional cardiologists’ guidance. The patients were followed for a duration of 1 month, and 6 months. Six SNPs were selected for genotyping including CYP2C19*2 (c.681G > A), CYP2C19*3 (c.636G > A), CYP2C19*17 allele (c.−806C > T), ABCB1 (c.3435C > T), CYP3A5 (c.6986A > G), and CYP3A4 (c.1026 + 12G > A). The mean loading dose was 600 mg/day in 267 (68.8%) individuals, 300 mg/day in 121 (31.2%). 8 patients had cardiovascular events such as thrombosis, unstable angina, and non-STEMI. The studied alleles and genotypes were in Hardy–Weinberg equilibrium. None of the SNPs individually were significantly associated with outcome events. Our results indicate that combinations of different alleles of genes are involved in pharmacokinetic variability and joint factors are important; this means that genotyping and analysis of an individual variant may not be as straightforward in risk assessment and pharmacogenetics. This highlights the importance of personalized medicine in risk assessment and treatment.
KeywordsGenetic variants Polymorphism Clopidogrel Cardiovascular event
We would like to thank the staff of genetic laboratory at Rajaie Hospital. We would like to thank professor Edward Tuddenham for critical reading of the manuscript.
Compliance with Ethical Standards
Conflict of interest
The authors have no conflict of interest to declare in relation to this manuscript.
- 4.Farid, N. A., Payne, C. D., Small, D. S., Winters, K. J., Ernest, C. S. 2nd, Brandt, J. T., et al. (2007). Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently. Clinical Pharmacology & Therapeutics, 81, 735–741.CrossRefGoogle Scholar
- 6.Kazui, M., Nishiya, Y., Ishizuka, T., Hagihara, K., Farid, N. A., Okazaki, O., et al. (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 Metabolism and Disposition, 38, 92–99.CrossRefPubMedGoogle Scholar
- 7.Geiger, J., Brich, J., Honig-Liedl, P., Eigenthaler, M., Schanzenbacher, P., Herbert, J. M., et al. (1999). Specific impairment of human platelet P2Y(AC) ADP receptor-mediated signaling by the antiplatelet drug clopidogrel. Arteriosclerosis, Thrombosis, and Vascular Biology, 19, 2007–2011.CrossRefPubMedGoogle Scholar
- 8.Kushner, F. G., Hand, M., Smith, S. C. Jr., King, S. B. 3rd, Anderson, J. L., Antman, E. M., et al. (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, 2271–2306.CrossRefPubMedGoogle Scholar
- 12.Brandt, J. T., Close, S. L., Iturria, S. J., Payne, C. D., Farid, N. A., Ernest, C. S. 2nd, et al. (2007). Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. Journal of Thrombosis and Haemostasis, 5, 2429–2436.CrossRefPubMedGoogle Scholar
- 16.Mega, J. L., Close, S. L., Wiviott, S. D., Shen, L., Walker, J. R., Simon, T., et al. (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, 1312–1319.CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Angiolillo, D. J., Fernandez-Ortiz, A., Bernardo, E., Ramirez, C., Cavallari, U., Trabetti, E., et al. (2006). Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel. Arteriosclerosis, Thrombosis, and Vascular Biology, 26, 1895–1900.CrossRefPubMedGoogle Scholar
- 21.Hoffmeyer, S., Burk, O., von Richter, O., Arnold, H. P., Brockmoller, J., Johne, A., et al. (2000). Functional polymorphisms of the human multidrug-resistance gene: Multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proceedings of the National Academy of Sciences of the United States of America, 97, 3473–3478.CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Karazniewicz-Lada, M., Danielak, D., Rubis, B., Burchardt, P., Oszkinis, G., & Glowka, F. (2014). The influence of genetic polymorphism of Cyp2c19 isoenzyme on the pharmacokinetics of clopidogrel and its metabolites in patients with cardiovascular diseases. The Journal of Clinical Pharmacology, 54, 874–880.CrossRefPubMedGoogle Scholar
- 24.Danielak, D., Karazniewicz-Lada, M., Wisniewska, K., Bergus, P., Burchardt, P., Komosa, A., et al. (2017). Impact of CYP3A4*1G Allele on clinical pharmacokinetics and pharmacodynamics of clopidogrel. The European Journal of Drug Metabolism and Pharmacokinetics, 42, 99–107.CrossRefPubMedGoogle Scholar
- 25.Amin, A. M., Sheau Chin L., Azri Mohamed Noor D., Kader S. A., Ali M., Kah Hay Y, et al. (2017). The personalization of clopidogrel antiplatelet therapy: The role of integrative pharmacogenetics and pharmacometabolomics. Cardiology Research and Practice 2017, 8062796.CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Schwab, M., Schaeffeler, E., Klotz, U., & Treiber, G. (2004). CYP2C19 polymorphism is a major predictor of treatment failure in white patients by use of lansoprazole-based quadruple therapy for eradication of Helicobacter pylori. Clinical Pharmacology & Therapeutics, 76, 201–209.CrossRefGoogle Scholar
- 29.Sim, S. C., Risinger, C., Dahl, M. L., Aklillu, E., Christensen, M., Bertilsson, L., et al. (2006). A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clinical Pharmacology & Therapeutics, 79, 103–113.CrossRefGoogle Scholar
- 30.Wallentin, L., James, S., Storey, R. F., Armstrong, M., Barratt, B. J., Horrow, J., et al. (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, 1320–1328.CrossRefPubMedGoogle Scholar
- 34.Olesen, J. B., Gislason, G. H., Charlot, M. G., Fosbol, E. L., Andersson, C., Weeke, P., et al. (2011). Calcium-channel blockers do not alter the clinical efficacy of clopidogrel after myocardial infarction: A nationwide cohort study. Journal of the American College of Cardiology, 57, 409–417.CrossRefPubMedGoogle Scholar
- 35.Sarafoff, N., Neumann, L., Morath, T., Bernlochner, I., Mehilli, J., Schomig, A., et al. (2011). Lack of impact of calcium-channel blockers on the pharmacodynamic effect and the clinical efficacy of clopidogrel after drug-eluting stenting. American Heart Journal, 161, 605–610.CrossRefPubMedGoogle Scholar