NFLUENCE OF CYP4F2*3 ON RESPONSE TO CLOPIDOGREL IN PATIENTS WITH ACUTE CORONARY SYNDROME

Background. Carriership of CYP4F2*3 (rs2108622, Val433Met) allelic variant can affect antiplatelet effect of clopidogrel, thus changing efficacy and safety of its standard dose.

Aim. To study the impact of carriership of at least one CYP4F2*3 allele on the risk of resistance to clopidogrel in patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention (PCI).

Material and methods. The study enrolled 81 patients with ACS and PCI: 64 males and 17 females, mean age 63.9±10.9 years. CYP4F2 allelic variants were detected by the method of real-time polymerase chain reaction. Platelet functional activity was evaluated by a portative aggregometer – the VerifyNow P2Y12 assay.

Results. Pharmacogenetic testing showed that 40 (49.4%) of ACS patients had normal genotype (CC), 38 (46.9%) patients were carriers of one associated with reduced drug metabolism allele (CT genotype), and 3 (3.7%) patients were homozygotes for T (TT genotype). Genotype and allele distribution was in the Hardy-Weinberg equilibrium (c2=2.79; p=0.095). There were no statistically significant differences in CYP4F2*3 allele frequency between patients that are resistant to clopidogrel (PRU>208) and in patients with a normal response to clopidogrel (PRU<208): 36.8% vs 54.8% (р=0.17). Average platelet reactivity units (PRU) and average platelet inhibition (%) in patients with and without T allelic variant of CYP4F2 also were not significantly different: 165.34±51.03 PRU vs 174.8±51.06 PRU (p=0.407), respectively, and 29.51±21.59% vs 27.72±18.35%, respectively (p=0.69).

Conclusion. Carriership of CYP4F2*3 allelic variant does not affect antiplatelet effect of clopidogrel in ACS patients. Further research on larger samples is needed to determine the role of CYP4F2 polymorphisms in personalization of clopidogrel antiplatelet therapy.

1. The top 10 causes of death. Fact sheet. Updated January 2017. Available at: http://www.who.int/mediacentre/ factsheets/fs310/en/. Checked by Feb 10, 20018.

2. Montalescot G, Sechtem U, Achenbach S, et al. ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013;34(38):2949-3003. doi: 10.1093/eurheartj/eht296.

3. Steg PG, James SK, Atar D, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Eur Heart J. 2012;33(20):2569-619. doi: 10.1093/eurheartj/ehs215.

4. Hamm CW, Bassand JP, Agewall S, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation:the Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2011;32(23):2999-3054. doi: 10.1093/eurheartj/ehr236.

5. Mantelescot G., Wiviott S., Braunwald E. et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet. 2009;373:723—31. doi: 10.1016/S01406736(09)60441-4.

6. Wallentin L, Becker RC, Budaj A, et al.; PLATO Investigators. Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes. N Engl J Med. 2009 Sep 10;361(11):1045-57. doi: 10.1056/NEJMoa0904327.

7. Elsenberg EH, van Werkum JW, van de Wal RM, et al. The influence of clinical characteristics, laboratory and inflammatory markers on ’high on-treatment platelet reactivity’ as measured with different platelet function tests. Thromb Haemost. 2009;102:719-27. . doi: 10.1160/TH09-05-0285.

8. Voisin S, Bongard V, Tidjane MA, et al. Are P2Y12 reaction unit (PRU) and % inhibition index equivalent for the expression of P2Y12 inhibition by the VerifyNow assay? Role of haematocrit and haemoglobin levels. Thromb Haemost. 2011;106(2):227-9. doi: 10.1160/TH11-01-0046.

9. Gurbel PA, Bliden KP, Hiatt BL, et al. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation. 2003;107:2908-13. doi: 10.1161/01.CIR.0000072771.11429.83.

10. Serebruany VL, Steinhubl SR, Berger PB, et al. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol. 2005;45:246-51. doi: 10.1016/j.jacc.2004.09.067.

11. Mega J.L., Simon T., Collet J.P. 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):1821-30. doi: 10.1001/jama.2010.1543.

12. 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;38:92-9. doi: 10.1124/dmd.109.029132.

13. Clopidogrel. Overwiev PharmGKB. Available at: https://www.pharmgkb.org/chemical/PA449053 #tabview=tab1&subtab=31. Checked by Feb 10, 20018.

14. Kupstyte N, Zaliunas R, Tatarunas V, et al. Effect of clinical factors and gene polymorphism of CYP2C19*2, *17 and CYP4F2*3 on early stent thrombosis. Pharmacogenomics. 2015;16(3):1819. doi: 10.2217/pgs.14.165.

15. Tatarunas V, Jankauskiene L, Kupstyte N, et al. The role of clinical parameters and of CYP2C19 G681 and CYP4F2G1347A polymorphisms on platelet reactivity during dual antiplatelet therapy. Blood Coagul Fibrinolysis. 2014;25(4):369-74. doi: 10.1097/MBC.0000000000000053.

16. Tatarunas V, Kupstyte N, Zaliunas R, et al. The impact of clinical and genetic factors on ticagrelor and clopidogrel antiplatelet therapy. Pharmacogenomics. 2017;18(10):969-79. doi: 10.2217/pgs2017-0070.

17. Sibbing D, Steinhubl SR, Schulz S, et al. Platelet aggregation and its association with stent thrombosis and bleeding in clopidogrel-treated patients: initial evidence of a therapeutic window. J Am Coll Cardiol. 2010;56:317-8. doi: 10.1016/j.jacc.2010.03.048.

18. Beilin L, Croft K, Mori T. et al. The influence of a single nucleotide polymorphism in the CYP4F2 gene on platelet epoxyeicosatrienoic acids and platelet aggregation. Available at: http://issfal2014.conferencespot. org/53974-ha-1.1180093/t-002-1.1181977/f-020-1.1182049/a-0191.1182050/ap-082-1.1182054. Checked by Feb 10, 20018.

19. Shuldiner A.R., O’Connell J.R., Bliden K.P. et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. J Am Med Assoc. 2009;302:849-57. doi: 10.1001/jama.2009.1232.

20. Hochholzer W., Trenk D., Fromm M.F. et al. Impact of cytochrome P450 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement. J Am Coll Cardiol. 2010;55:2427-34. doi: 10.1016/j.jacc.2010.02.031.

21. Komarov A.L., Shahmatova O.O., Iljushhenko T.A., et al. Assessing Risk of Cardiovascular Events in Clopidogrel-Treated Patients with Stable CHD: Platelet Function or Genetic Testing? Doktor.Ru. 2012;6:11-19. (In Russ.) [Комаров А.Л., Шахматова О.О., Илющенко Т.А., и др. Оценка риска сердечно-сосудистых осложнений у больных стабильной ИБС, получающих клопидогрел: функция тромбоцитов или генетические исследования? Доктор.Ру. 2012;6:11-19].

22. Goluhova E.Z., Grigorjan M.V., Rjabinina M.N., et al. The platelet reactivity after percutaneous coronary intervention in patients with double antiplatelet therapy: impact of genetic polymorphisms. Kreativnaja Kardiologija. 2014;3:39-52. (In Russ.) [Голухова Е.З., Григорян М.В., Рябинина М.Н., и др. Современные аспекты фармакогенетики клопидогрела и его клиническое значение. Креативная Кардиология. 2014;3:39-52].

23. Mazurov A.V., Zjurjaev I.T., Haspekova S.G., et al. Factors influencing platelet aggregation in patients with acute coronary syndrome. Ter Arkhiv. 2014;9:83-9. (In Russ.) [Мазуров А.В., Зюряев И.Т., Хаспекова С.Г., и др. Факторы, влияющие на агрегационную активность тромбоцитов у больных с острым коронарным синдромом. Терапевтический Архив. 2014;9:83-9].

24. Mirzaev K.B., Kazakov R.E., Smirnov V.V., et al. Influence of the CYP3A4 isoenzyme metabolic activity and CYP2C19 gene polymorphisms on clopidogrel antiplatelet effect in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Rational Pharmacotherapy in Cardiology. 2015;11:344-54. (In Russ.) [Мирзаев К.Б., Казаков Р.Е., Смирнов В.В., и др. Влияние метаболической активности изофермента CYP3A4 и полиморфных маркеров гена CYP2C19 на антиагрегантный эффект клопидогрела у больных с острым коронарным синдромом, перенесших чрескожное коронарное вмешательство. Рациональная Фармакотерапия в Кардиологии. 2015;11:344-54].

25. Galyavich AS, Valeyeva DD, Minnetdinov RSh, et al. CYP2C19 gene polymorphism in patients with myocardial infarction who use clopidogrel. Kardiologiia. 2012;4:20-4. (In Russ.) [Галявич А.С., Валеева Д.Д., Миннетдинов Р.Ш. и др. Полиморфизм гена CYP2C19 у больных инфарктом миокарда, применяющих клопидогрел. Кардиология. 2012;4:20-4].

26. Sumarokov AB, Meshkov AN, Buryachkovskaya LI, et al. Polymorphism 416 Т>С of gene CYP2C9 and sensitivity to clopidogrel. Tromboz, Gemostazireologiya. 2014;1:53-61. (In Russ.) [Сумароков А.Б., Мешков А.Н., Бурячковская Л.И., и др. Полиморфизм 416Т>С гена CYP2C9 и чувствительность к клопидогрелю. Тромбоз, Гемостазиреология. 2014;1:53-61].