The impact of CYP4F2, ABCB1, and GGCX polymorphisms on bleeding episodes associated with acenocoumarol in Russian patients with atrial fibrillation
-
Dmitriy Alexeyevich Sychev
,
Ruslan Evgenyevich Kazakov
Abstract
Background:
Oral anticoagulants are commonly used to treat patients with thromboembolic pathology. Genetic variations could influence personal response to anticoagulant drugs. Acenocoumarol (AC) is a vitamin K antagonist used in anticoagulant therapy and as a prophylaxis measure in Europe. In this study, we assessed the effect of CYP4F2 rs2108622, ABCB1, and GGCX polymorphisms on the safety profile and regime dosing of AC in patients with nonvalvular atrial fibrillation.
Methods:
Fifty patients aged 40–70 years were included. All patients received AC in the dose of 1–6 mg daily with a target international normalized ratio of 2.0–3.0. Genotyping for polymorphism markers C3435T for the ABCB1 gene, rs2108622 for the CYP4F2 gene, and rs11676382 for the GGCX gene were designed using polymerase chain reaction and restriction fragment length polymorphism. Statistical analysis was performed using the Fisher exact test and the Mann-Whitney U test.
Results:
We found that CYP4F2 rs2108622 CT carriers required a higher AC dose than CC (p=0.0366), and CT and TT carriers required a higher AC dose than CC (p=0.0314).
Conclusions:
We found that ABCB1 CT and TT genotypes are associated with a higher risk of bleeding. No influence of ABCB1 and GGCX polymorphisms on the doses of AC was established. CYP4F2 could still be a genetic factor responsible for the personal variability of AC metabolism.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Chugh SS, Roth GA, Gillum RF, Mensah GA. Global burden of atrial fibrillation in developed and developing nations. Glob Heart 2014;9:113–9.10.1016/j.gheart.2014.01.004Search in Google Scholar PubMed
2. Ment J. Direct oral anticoagulants: key considerations for use to prevent stroke in patients with nonvalvular atrial fibrillation. Vasc Health Risk Manag 2015;317. Available at: http://www.dovepress.com/direct-oral-anticoagulants-key-considerations-for-use-to-prevent-strok-peer-reviewed-article-VHRM.10.2147/VHRM.S79065Search in Google Scholar PubMed PubMed Central
3. Riva N, Donadini MP, Ageno W. Epidemiology and pathophysiology of venous thromboembolism: similarities with atherothrombosis and the role of inflammation. Thromb Haemost 2014;113:1176–83.10.1160/TH14-06-0563Search in Google Scholar PubMed
4. Shi X-X, Ren G-H, Wang J, Zhang N, Yu M-Z, Wang Y-Q, et al. Effectiveness and safety of warfarin and anti-platelet drugs for the primary prevention of stroke in patients with non-valvular atrial fibrillation: a meta-analysis. Int J Clin Exp Med 2015;8:8384–97.Search in Google Scholar
5. Torn M, Bollen WL, van der Meer FJ, van der Wall EE, Rosendaal FR. Risks of oral anticoagulant therapy with increasing age. Arch Intern Med 2005;165:1527–32.10.1001/archinte.165.13.1527Search in Google Scholar PubMed
6. Uehara S, Uno Y, Inoue T, Kawano M, Shimizu M, Toda A, et al. Individual differences in metabolic clearance of S-warfarin efficiently mediated by polymorphic marmoset cytochrome P450 2C19 in livers. Drug Metab Dispos 2016;44:911–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27098744.10.1124/dmd.116.070383Search in Google Scholar PubMed
7. Li X, Yang J, Wang X, Xu Q, Zhang Y, Yin T. Clinical benefits of pharmacogenetic algorithm-based warfarin dosing: meta-analysis of randomized controlled trials. Thromb Res 2015;135:621–9.10.1016/j.thromres.2015.01.018Search in Google Scholar PubMed
8. Sontag TJ, Parker RS. Cytochrome P450 omega-hydroxylase pathway of tocopherol catabolism. Novel mechanism of regulation of vitamin E status. J Biol Chem 2002;277:25290–6.10.1074/jbc.M201466200Search in Google Scholar PubMed
9. Sontag TJ, Parker RS. Influence of major structural features of tocopherols and tocotrienols on their omega-oxidation by tocopherol-omega-hydroxylase. J Lipid Res 2007;48:1090–8.10.1194/jlr.M600514-JLR200Search in Google Scholar PubMed
10. Ejsing TB, Morling N, Linnet K. A review on the relation between the brain-serum concentration ratio of drugs and the influence of P-glycoprotein. Drug Metabol Drug Interact 2007;22:113–29.10.1515/DMDI.2007.22.2-3.113Search in Google Scholar PubMed
11. Wadelius M, Sörlin K, Wallerman O, Karlsson J, Yue Q-Y, Magnusson PK, et al. Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors. Pharmacogenomics J 2004;4:40–8.10.1038/sj.tpj.6500220Search in Google Scholar PubMed
12. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmöller J, Johne A, et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 2000;97:3473–8.10.1073/pnas.97.7.3473Search in Google Scholar PubMed PubMed Central
13. Rozhkov A, Sychev DA, Kazakov RE. ABCB1 polymorphism and acenocoumarol safety in patients with valvular atrial fibrillation. Int J Risk Saf Med 2015;27(Suppl 1):S15–6.10.3233/JRS-150672Search in Google Scholar PubMed
14. Furie B, Bouchard BA, Furie BC. Vitamin K-dependent biosynthesis of gamma-carboxyglutamic acid. Blood 1999;93:1798–808.10.1182/blood.V93.6.1798.406k22_1798_1808Search in Google Scholar
15. Whitlock RP, Sun JC, Fremes SE, Rubens FD, Teoh KH, American College of Chest Physicians. Antithrombotic and thrombolytic therapy for valvular disease: antithrombotic therapy and prevention of thrombosis. In: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 9th ed. Chest [Internet] 2012;141(Suppl 2):e576S–600S. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22315272.10.1378/chest.11-2305Search in Google Scholar PubMed PubMed Central
16. ROCKET AF Study Investigators. Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study. Am Heart J 2010;159:340–7.e1.10.1016/j.ahj.2009.11.025Search in Google Scholar PubMed
17. Butler JM, Reeder DJ. Detection of DNA polymorphisms using PCR-RFLP and capillary electrophoresis. In: Capillary Electrophoresis of Nucleic Acids [Internet]. New Jersey: Humana Press; p. 49–56. Available at: http://link.springer.com/10.1385/1-59259-116-7:49.10.1385/1-59259-116-7:49Search in Google Scholar
18. Scott SA, Khasawneh R, Peter I, Kornreich R, Desnick RJ. Combined CYP2C9, VKORC1 and CYP4F2 frequencies among racial and ethnic groups. Pharmacogenomics 2010;11:781–91.10.2217/pgs.10.49Search in Google Scholar PubMed PubMed Central
19. King CR, Deych E, Milligan P, Eby C, Lenzini P, Grice G, et al. Gamma-glutamyl carboxylase and its influence on warfarin dose. Thromb Haemost 2010;104:750–4.10.1160/TH09-11-0763Search in Google Scholar PubMed PubMed Central
20. Danese E, Montagnana M, Johnson JA, Rettie AE, Zambon CF, Lubitz SA, et al. Impact of the CYP4F2 p.V433M polymorphism on coumarin dose requirement: systematic review and meta-analysis. Clin Pharmacol Ther 2012;92:746–56.10.1038/clpt.2012.184Search in Google Scholar PubMed PubMed Central
21. Perez-Andreu V, Roldan V, Anton AI, Garcia-Barbera N, Corral J, Vicente V, et al. Pharmacogenetic relevance of CYP4F2 V433M polymorphism on acenocoumarol therapy. Blood 2009;113:4977–9.10.1182/blood-2008-09-176222Search in Google Scholar PubMed
22. Wypasek E, Branicka A, Awsiuk M, Sadowski J, Undas A. Genetic determinants of acenocoumarol and warfarin maintenance dose requirements in Slavic population: a potential role of CYP4F2 and GGCX polymorphisms. Thromb Res 2014;134:604–9.10.1016/j.thromres.2014.06.022Search in Google Scholar PubMed
23. Saraeva RB, Paskaleva ID, Doncheva E, Eap CB, Ganev VS. Pharmacogenetics of acenocoumarol: CYP2C9, CYP2C19, CYP1A2, CYP3A4, CYP3A5 and ABCB1 gene polymorphisms and dose requirements. J Clin Pharm Ther 2007;32:641–9.10.1111/j.1365-2710.2007.00870.xSearch in Google Scholar PubMed
24. Hodges LM, Markova SM, Chinn LW, Gow JM, Kroetz DL, Klein TE, et al. Very important pharmacogene summary. Pharmacogenet Genomics 2011;21:152–61.10.1097/FPC.0b013e3283385a1cSearch in Google Scholar PubMed PubMed Central
25. Verhoef TI, Ragia G, de Boer A, Barallon R, Kolovou G, Kolovou V, et al. A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon. N Engl J Med 2013;369:2304–12.10.1056/NEJMoa1311388Search in Google Scholar PubMed
26. Verhoef TI, Redekop WK, Daly AK, van Schie RM, de Boer A, Maitland-van der Zee A-H. Pharmacogenetic-guided dosing of coumarin anticoagulants: algorithms for warfarin, acenocoumarol and phenprocoumon. Br J Clin Pharmacol 2014;77: 626–41.10.1111/bcp.12220Search in Google Scholar PubMed PubMed Central
27. Pengo V, Pegoraro C, Cucchini U, Iliceto S. Worldwide management of oral anticoagulant therapy: the ISAM study. J Thromb Thrombolysis 2006;21:73–7.10.1007/s11239-006-5580-ySearch in Google Scholar PubMed
28. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ, American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: antithrombotic therapy and prevention of thrombosis. In: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 9th ed. Chest [Internet]. 2012;141(2 Suppl):7S–47S. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22315257.10.1378/chest.1412S3Search in Google Scholar PubMed PubMed Central
29. Carcas AJ, Borobia AM, Velasco M, Abad-Santos F, Díaz MQ, Fernández-Capitán C, et al. Efficiency and effectiveness of the use of an acenocoumarol pharmacogenetic dosing algorithm versus usual care in patients with venous thromboembolic disease initiating oral anticoagulation: study protocol for a randomized controlled trial. Trials 2012;13:239.10.1186/1745-6215-13-239Search in Google Scholar PubMed PubMed Central
30. Jiménez-Varo E, Cañadas-Garre M, Henriques CI, Pinheiro AM, Gutiérrez-Pimentel MJ, Calleja-Hernández MÁ. Pharmacogenetics role in the safety of acenocoumarol therapy. Thromb Haemost 2014;112:522–36.10.1160/TH13-11-0941Search in Google Scholar PubMed
31. Jiménez-Varo E, Cañadas-Garre M, Gutiérrez-Pimentel MJ, Calleja-Hernández MA. Prediction of stable acenocoumarol dose by a pharmacogenetic algorithm. Pharmacogenet Genomics 2014;24:501–13.10.1097/FPC.0000000000000082Search in Google Scholar PubMed
32. An SH, Chang BC, Lee KE, Gwak HS. Influence of UDP-Glucuronosyltransferase polymorphisms on stable warfarin doses in patients with mechanical cardiac valves. Cardiovasc Ther 2015;33:324–8.10.1111/1755-5922.12147Search in Google Scholar PubMed
33. de Oliveira Almeida VC, Ribeiro DD, Gomes KB, Godard AL. Polymorphisms of CYP2C9, VKORC1, MDR1, APOE and UGT1A1 genes and the therapeutic warfarin dose in Brazilian patients with thrombosis: a prospective cohort study. Mol Diagn Ther 2014;18:675–83.10.1007/s40291-014-0121-4Search in Google Scholar PubMed
©2016 Walter de Gruyter GmbH, Berlin/Boston
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- Pharmacogenetic approach to losartan in Marfan patients: a starting point to improve dosing regimen?
- Altered pharmacokinetics of rosiglitazone in a mouse model of non-alcoholic fatty liver disease
- The impact of CYP4F2, ABCB1, and GGCX polymorphisms on bleeding episodes associated with acenocoumarol in Russian patients with atrial fibrillation
Articles in the same Issue
- Frontmatter
- Review
- Pharmacogenomics in pain treatment
- Original Articles
- Association study of DRD2 A2/A1, DRD3 Ser9Gly, DβH −1021C>T, OPRM1 A118G and GRIK1 rs2832407C>A polymorphisms with alcohol dependence
- Medication therapy management (MTM): an innovative approach to improve medication adherence in diabetics
- Pharmacogenetic approach to losartan in Marfan patients: a starting point to improve dosing regimen?
- Altered pharmacokinetics of rosiglitazone in a mouse model of non-alcoholic fatty liver disease
- The impact of CYP4F2, ABCB1, and GGCX polymorphisms on bleeding episodes associated with acenocoumarol in Russian patients with atrial fibrillation
