CYP2C19 and ABCB1 polymorphisms in patients of Chuvash ethnic group: assessment of clopidogrel resistance and associations with recurrent myocardial infarction

Background. The prevalence of clopidogrel resistance among patients with cardiovascular diseases (CVD) reaches 30–40 %, significantly increasing the risk of recurrent myocardial infarction (MI) and other thrombotic events. Genetic polymorphisms in CYP2C19 and ABCB1 account for up to 40 % of the variability in antiplatelet response; however, data on Turkic populations, including the Chuvash, remain fragmentary.

Objective. To determine the frequencies of CYP2C19 (*2, *3, *17) and ABCB1 C3435T polymorphisms, as well as their association with recurrent MI and clopidogrel resistance in patients of Chuvash ethnic origin with CVD, including acute coronary syndrome (ACS).

Materials and methods. This prospective cohort study included 216 Chuvash patients (mean age 66.5 years) with CVD, including ACS, receiving dual antiplatelet therapy with clopidogrel. Genotyping of CYP2C19 (*2, *3, *17) and ABCB1 (3435C>T) polymorphisms was performed using real-time PCR. In a subgroup of ACS patients (n=30), ADP-induced platelet aGGreGAtion was assessed turbidimetrically on day 7 of therapy.

Results. Among Chuvash patients, a high frequency of minor alleles was observed: ABCB1 C3435T — 60.6 %, CYP2C1917 (–806C>T) — 28.7 %, whereas the frequencies of CYP2C192 and CYP2C193 were low (9.05 % and 1.85 %, respectively). Heterozygous CT genotype of CYP2C19*17 was associated with a higher rate of recurrent MI both in the overall cohort (19.8 % vs. 8.5 % in CC carriers; p=0.049) and in the ACS subgroup (30.2 % vs. 12.9 %; p=0.037, p~CC–CT~ =0.044). Laboratory platelet aGGreGAtion assessment revealed that the highest proportion of antiplateletresistant patients was observed among heterozygotes carrying the *1/*17 genotype (rapid metabolizer phenotype), whereas no resistance cases were recorded among *17/*17 homozygotes (ultrarapid metabolizers). No statistically significant associations with recurrent MI were found for CYP2C192, CYP2C193, or ABCB1 polymorphisms.

Conclusion. In Chuvash patients with CVD, including ACS, heterozygous carriage of CYP2C1917 is associated with recurrent MI, which contradicts the expected enhancement of clopidogrel antiplatelet effect (rapid metabolizer phenotype). This may indicate possible phenoconversion due to the interplay of genetic factors (ABCB1 C3435T) and drug — drug interactions (concomitant omeprazole use).

1. Lewis JP, Stephens SH, Horenstein RB, et al. The CYP2C19*17 variant is not independently associated with clopidogrel response. J Thromb Haemost. 2013 Sep;11(9):1640-6. doi: 10.1111/jth.12342.

2. 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 Oct 1;108(7): 2244-7. doi: 10.1182/blood-2006-04-013052.

3. Dello Russo C, Frater I, Kuruvilla R, et al. CYP2C19 genotype testing for clopidogrel: A guideline developed by the UK Centre of Excellence in Regulatory Science and Innovation in Pharmacogenomics (CERSI-PGx). Br J Clin Pharmacol. 2026 Feb;92(2):329-347. doi: 10.1002/bcp.70370.

4. Huang B, Cui DJ, Ren Y, et al. Effect of cytochrome P450 2C19*17 allelic variant on cardiovascular and cerebrovascular outcomes in clopidogrel-treated patients: A systematic review and meta-analysis. J Res Med Sci. 2017 Sep 26;22:109. doi: 10.4103/jrms.JRMS_590_16.

5. Zhuo ZL, Xian HP, Long Y, et al. Association between CYP2C19 and ABCB1 polymorphisms and clopidogrel resistance in clopidogrel-treated Chinese patients. Anatol J Cardiol. 2018 Feb;19(2):123-129. doi: 10.14744/AnatolJCardiol.2017.8097.

6. Kitaeva EYu, Shprakh VV, Mirzaev KB, et al. Frequency of CYP2C19 and ABCB1 genes polymorphisms, associated with the change, caused by clopidogrel antiagregant among the Russians and the Buryats. Siberian Medical Review. 2018;(3):43-50. (In Russ.).

7. Mirzaev K.B., Sychev D.A., Andreev D.A. Ethnic characteristics of the CYP2C19 gene polymorphism associated with impaired response to clopidogrel in the Russian Federation. Molecular Medicine. 2014;1:13-21. (In Russ.).

8. Li Y, Tang HL, Hu YF, Xie HG. The gain-of-function variant allele CYP2C19*17: a double-edged sword between thrombosis and bleeding in clopidogrel-treated patients. J Thromb Haemost. 2012 Feb;10(2):199-206. doi: 10.1111/j.1538-7836.2011.04570.x.

9. Sibbing D, Koch W, Gebhard D, et al. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation. 2010 Feb 2;121(4):512-8. doi: 10.1161/CIRCULATIONAHA.109.885194.

10. Applied Pharmacogenetics: monograph / [Sychev D. A., Abdullaev Sh. P., Ametov A. S. [et al.]]; edited by D. A. Sychev. - Moscow: Triada, 2021. - 494 p.: ill.: 25 cm; ISBN 978-5-94789-982-5. (In Russ.).

11. All-Russian Population Census 2020. Results of the All-Russian Population Census 2020. Volume 5: Ethnic Composition and Language Proficiency. https://rosstat.gov.ru/vpn/2020/Tom5_Nacionalnyj_sostav_i_vladenie_yazykami

12. Georgieva KS, Pavlova SI, Zhuchkova SM. Resistance to antiplatelets in patients with acute coronary event: pharmacogenetic aspects and drug interactions. Experimental and Clinical Pharmacology. 2024;87(2):20–26. (In Russ.).

13. Makeeva O, Stepanov V, Puzyrev V, et al. Global pharmacogenetics:geneticsubstructureofEurasian populations and its effect on variants of drug-metabolizing enzymes. Pharmacogenomics. 2008 Jul;9(7):847-68. doi: 10.2217/14622416.9.7.847.

14. Vasilyev FF, Danilova DA, Kaimonov VS, et al. Frequency distribution of polymorphisms of CYP2C19, CYP2C9, VKORC1 and SLCO1B1 genes in the Yakut population. Res Pharm Sci. 2016 May-Jun;11(3):259-64.

15. Shuev G.N., Sychev D.A., Suleymanov S.Sh., et al. Comparison of CYP2C9, CYP2C19, CYP2D6, ABCB1, SLCO1B1 gene polymorphism frequency in Russian and Nanai populations. Pharmacogenetics and Pharmacogenomics. 2016;(2):12-18. (In Russ.).

16. Lee CR, Luzum JA, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 Genotype and Clopidogrel Therapy: 2022 Update. Clin Pharmacol Ther. 2022 Nov;112(5):959-967. doi: 10.1002/cpt.2526.

17. Pratt VM, Cavallari LH, Fulmer ML, et al. CYP3A4 and CYP3A5 Genotyping Recommendations: A Joint Consensus Recommendation of the Association for Molecular Pathology, Clinical Pharmacogenetics Implementation Consortium, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, European Society for Pharmacogenomics and Personalized Therapy, and Pharmacogenomics Knowledgebase. J Mol Diagn. 2023 Sep;25(9):619-629. doi: 10.1016/j.jmoldx.2023.06.008.

18. Gross L, Trenk D, Jacobshagen C, et al. Genotype-Phenotype Association and Impact on Outcomes following Guided De-Escalation of Anti-Platelet Treatment in Acute Coronary Syndrome Patients: The TROPICAL-ACS Genotyping Substudy. Thromb Haemost. 2018 Sep;118(9):1656- 1667. doi: 10.1055/s-0038-1667337.

19. Markova A.S., Mirzaev K. B., Sychev D.A., et al. The role of CYP2C19 gene nucleotide sequence variants in assessing response to P2Y12 receptor inhibitor antiplatelet therapy in old patients with acute coronary syndrome. Rational Pharmacotherapy in Cardiology. 2025;21(5):441-448. (In Russ.).

20. Vorobyov A.S., Lifshits G.I., Zelenskaya E.M., et al. Clinically significant CYP2C19 genotypes in patients with myocardial infarction in the northern region of Russia. Russian Journal of Cardiology. 2023;28(10):5533. (In Russ.).

21. Lenoir C, Niederer A, Rollason V, et al. Prediction of cytochromes P450 3A and 2C19 modulation by both inflammation and drug interactions using physiologically based pharmacokinetics. CPT Pharmacometrics Syst Pharmacol. 2022 Jan;11(1):30-43. doi: 10.1002/psp4.12730.