Genetic status of patients with myocardial infarction based on the results of KASP-analysis of gene polymorphisms associated with the metabolism of antithrombotic drugs

Objective. To conduct molecular genetic studies of patients with myocardial infarction (MI) for polymorphisms of genes associated with the metabolism of antithrombotic drugs, and to evaluate their relationship with clinical and laboratory parameters.

Materials and methods. The material for molecular genetic studies was venous blood of patients with acute MI who underwent percutaneous coronary intervention (PCI) with stenting of the infarct-related artery. This data sample included 69 patients, of which 58 (84.1%) were male and 11 (15.9%) were female.

The technology based on competitive allele-specific polymerase chain reaction (PCR) was used for genotyping. The analysis was performed for 26 polymorphisms of the genes CDC42BPA, RPS20P10, P2RY12, MED12L, PPM1K, LOC124900191, PACRG-AS1, LINC02854, SOCS5P1, ABCB1, PON1, NCOA2, CER1, LIPM, CYP2C18, CYP2C19, CYP2C9, CRTAC1, R3HCC1L, MICAL2, LOC105376637, CES1, ZFHX3-AS1 and WFDC1. The entire list of necessary clinical and laboratory tests was performed according to the protocols for examination and treatment of cardiovascular diseases of the Ministry of Health of the Republic of Belarus.

Statistical analysis was performed using Microsoft Excel and SPSS v.20.0. The study design was approved by the Ethics Committee of the Republican Scientific and Practical Center “Cardiology” and the Bioethics Committee of the Institute of Genetics and Cytology of the National Academy of Sciences of Belarus.

Results. In the presence of the minor allele G for the rs35835168 polymorphism, the level of alanine aminotransferase (ALT) was lower than in the presence of the CC genotype - 33.29 U / L and 55.45 U / L, respectively (p=0.023); in the presence of the minor allele G for the rs12598219 polymorphism, the atherogenic coefficient (AC) was higher than in the presence of the AA genotype - 4.66 and 3.79, respectively (p=0.032); in the presence of the GG genotype for the rs12598219 polymorphism, the prothrombin time (PT) was higher than in the presence of the alternative genotype - 19.50 and 12.30, respectively (p=0.002); in the presence of the TT genotype for the rs7584466 polymorphism, the PT indicator was higher than in the presence of the minor allele - 12.98 and 11.87, respectively (p=0.026); in the presence of the AA genotype for the rs303500 polymorphism, the thrombin time (TT) indicator was higher than in the presence of the alternative genotype - 17.99 and 15.30, respectively (p=0.039); in the presence of the AA genotype for the rs7714373 polymorphism, the TT indicator was higher than in the presence of the AG / GG genotypes - 24.75 and 16.38, respectively (p=0.018); For polymorphisms rs1799853, rs7584466, rs7714373 and rs139496757 there was an association with the fibrinogen level; in the presence of the minor allele A for rs7714373, the ASPI value was 15.82, in the presence of the GG genotype - 29.66 (p=0.003); in the presence of the CC genotype, the ASPI value was 62.00, which significantly exceeds the ASPI value in the presence of the CT/TT genotype - 24.92 (p=0.012).

Conclusion. Therefore, we identified associations between clinical and laboratory parameters of patients with MI and a number of polymorphisms rs12248560, rs12598219, rs139496757, rs1799853, rs303500, rs35835168, rs55670713, rs71546150, rs7584466 and rs7714373.

1. WHO. Cardiovascular diseases. [date of access 2024 Sept. 01]. Available from: https://www.who.int/ru/news-room/factsheets/detail/cardiovascular-diseases-(cvds) (In Russ.).

2. Barbarash OL, Kashtalap VV, Duration of dual antiplatelet therapy. Facts and assumptions. Russian Journal of Cardiology. 2016;(2):75-83. (In Russ.).

3. Sherwood MW, Wiviott SD, Peng SA, Roe MT, Delemos J, Peterson ED, et al. Early clopidogrel versus prasugrel use among contemporary STEMI and NSTEMI patients in the US: insights from the National Cardiovascular Data Registry. J Am Heart Assoc. 2014;3(2):e000849. DOI: https://doi.org/10.1161/JAHA.114.000849

4. Yan Y, Wang X, Fan JY, Nie SP, Raposeiras-Roubín S, Abu-Assi E, et al. Impact of concomitant use of proton pump inhibitors and clopidogrel or ticagrelor on clinical outcomes in patients with acute coronary syndrome. J Geriatr Cardiol. 2016;13(3):209-217. DOI: https://doi.org/10.11909/j.issn.1671-5411.2016.03.007

5. Ziegler S, Schillinger M, Funk M, Felber K, Exner M, Mlekusch W, et al. Association of a functional polymorphism in the clopidogrel target receptor gene, P2Y12, and the risk for ischemic cerebrovascular events in patients with peripheral artery disease. Stroke. 2005;36(7):1394-1399. DOI: https://doi.org/10.1161/01.STR.0000169922.79281.a5

6. Brandt JT, Close SL, Iturria SJ, Payne CD, Farid NA, Ernest CS, 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. DOI: https://doi.org/10.1111/j.1538-7836.2007.02775.x

7. Staritz P, Kurz K, Stoll M, Giannitsis E, Katus HA, Ivandic BT. Platelet reactivity and clopidogrel resistance are associated with the H2 haplotype of the P2Y12-ADP receptor gene. Int J Cardiol. 2009;133(3):341-345. DOI: https://doi.org/10.1016/j.ijcard.2007.12.118

8. Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Méneveau N, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N. Engl J Med. 2009;360(4):363-375. DOI: https://doi.org/10.1056/NEJMoa0808227

9. Mega JL, Close SL, Wiviott SD, Shen L, Walker JR, Simon T, et al. 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. 2010;16;376(9749):1312-1319. DOI: https://doi.org/10.1016/S0140-6736(10)61273-1

10. Lewis JP, Horenstein RB, Ryan K, O’Connell JR, Gibson Q, Mitchell BD, et al. The functional G143E variant of carboxylesterase 1 is associated with increased clopidogrel active metabolite levels and greater clopidogrel response. Pharmacogenet. Genomics. 2013;23(1):1-8. DOI: https://doi.org/10.1097/FPC.0b013e32835aa8a2

11. Park KW, Park JJ, Kang J, Jeon KH, Kang SH, Han JK, et al. Paraoxonase 1 gene polymorphism does not affect clopidogrel response variability but is associated with clinical outcome after PCI. PLoS One. 2013;8(2):e52779. DOI: https://doi.org/10.1371/journal.pone.0052779

12. Li X, Zhang L, Chen X, Qu F, Li J, Ma C, et al. PON1 Q192R genotype influences clopidogrel responsiveness by relative platelet inhibition instead of on-treatment platelet reactivity. Thromb. Res. 2013;132(4):444-449. DOI: https://doi.org/10.1016/j.thromres.2013.08.004

13. Zhang H, Kim MH, Guo LZ, Serebruany V. CYP2C19 but not CYP2B6, CYP3A4, CYP3A5, ABCB1, PON1 or P2Y12 genetic polymorphism impacts antiplatelet response after clopidogrel in Koreans. Blood Coagul Fibrinolysis. 2017;28(1):56-61. DOI: https://doi.org/10.1097/MBC.0000000000000536

14. Zhai Y, He H, Ma X, Xie J, Meng T, Dong Y, et al. Meta-analysis of effects of ABCB1 polymorphisms on clopidogrel response among patients with coronary artery disease. Eur J Clin Pharmacol. 2017;73(7):843-854. DOI: https://doi.org/10.1007/s00228-017-2235-1

15. Lee CR, Luzum JA, Sangkuhl K, Gammal RS, Sabatine MS, Stein CM, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 Genotype and Clopidogrel Therapy: 2022 Update. Clin Pharmacol Ther. 2022;112(5):959-967. DOI: https://doi.org/10.1002/cpt.2526

16. Verma SS, Luzum JA, Sangkuhl K, Gammal RS, Sabatine MS, Stein CM, et al. Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated with Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium. Clin Pharmacol Ther. 2020;108(5):1067-1077. DOI: https://ascpt.onlinelibrary.wiley.com/doi/10.1002/cpt.1911