Ethnic variations in warfarin pharmacogenetics: A comprehensive review

Gulnara Svyatova Yergali Miyerbekov Galina Berezina Alexandra Murtazaliyeva Rustem Tuleutayev   

Open Access   

Published:  Jan 04, 2025

DOI: 10.7324/JAPS.2025.201718
Abstract

The therapeutic dose of warfarin depends more on the patient’s genotype than on the type of disease. However, to date, no uniform algorithms have been developed for warfarin dosing in different nationalities. Hence, the study aims to evaluate and structure existing recommendations for warfarin prescription in different nations. A systematic search for the necessary information for 2011–2023 on the dosage of warfarin in different ethnic groups was conducted. The databases used for this search are PubMed, Embase, Scopus, Google Scholar, and Web of Science. The correlation between various genetic polymorphisms and the pharmacodynamics and pharmacokinetics of warfarin was revealed. This primarily refers to the presence of genes of the cytochrome P450 family and vitamin K epoxide reductase complex 1. At the same time, the necessity of studying the genes CYP2C19, and gamma-glutamyl carboxylase (GGCX) is discussed. These genes can significantly improve the accuracy of existing pharmacogenetic algorithms, although they may slightly increase the individual variability of warfarin dosing.


Keyword:     Genotype genetic polymorphism cytochrome pharmacodynamics algorithm


Citation:

Svyatova G, Miyerbekov Y, Berezina G, Murtazaliyeva A, Tuleutayev R. Ethnic variations in warfarin pharmacogenetics: A comprehensive review. J Appl Pharm Sci. 2025. Online First. http://doi.org/10.7324/JAPS.2025.201718

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

HTML Full Text

Reference

1. Lee KE, Yee J, Lee GY, Chung Je, Seong JM, Chang BC, et al. Genotype-guided warfarin dosing may benefit patients with mechanical aortic valve replacements: randomized controlled study. Sci Rep. 2020 Apr 24;10(1):6988. doi: https://doi.org/10.1038/s41598-020-63985-7

2. Fahmi AM, El Bardissy A, Saad MO, Elshafei MN, Bader L, Mahfouz A, et al. Clinical versus fixed warfarin dosing and the impact on quality of anticoagulation (The ClinFix trial). Clin Transl Sci. 2024 Jun;17(6):e13797. doi: https://doi.org/10.1111/cts.13797

3. Zhang S, Zhao M, Zhong S, Niu J, Zhou L, Zhu B, et al. Association between CYP2C9 and VKORC1 genetic polymorphisms and efficacy and safety of warfarin in Chinese patients. Pharmacogenet Genomics. 2024 Jun 1;34(4):105–16. doi: https://doi.org/10.1097/fpc.0000000000000526

4. Wang X, Zhao D, Ma J, Wang X, Liu J. Correlation between metabolic parameters and warfarin dose in patients with heart valve replacement of different genotypes. Rev Cardiovasc Med. 2024 Apr;25(4):128. doi: https://doi.org/10.31083/j.rcm2504128

5. Hirai T, Aoyama T, Tsuji Y, Itoh T, Matsumoto Y, Iwamoto T. Kinetic-pharmacodynamic model of warfarin for prothrombin time-international normalized ratio in Japanese patients. Br J Clin Pharmacol. 2024 Mar;90(3):828–36. doi: https://doi.org/10.1111/bcp.15967

6. Anand A, Hegde N, Chhabra P, Purohit J, Kumar R, Gupta A, et al. Pharmacogenetic guided versus standard warfarin dosing for routine clinical care with its pharmacoeconomic impact: a randomized controlled clinical trial. Ann Hematol. 2024 Jun;103(6):2133–44. doi: https://doi.org/10.1007/s00277-024-05757-1

7. Sridharan K, Sivaramakrishnan G. A network meta-analysis of CYP2C9, CYP2C9 with VKORC1 and CYP2C9 with VKORC1 and CYP4F2 genotype-based warfarin dosing strategies compared to traditional. J Clin Pharm Ther. 2021 Jun;46(3):640–8. doi: https://doi.org/10.1111/jcpt.13334

8. Xie C, Xue L, Zhang Y, Zhu J, Zhou L, Hang Y, et al. Comparison of the prediction performance of different warfarin dosing algorithms based on Chinese patients. Pharmacogenomics. 2020 Jan;21(1):23–32. doi: https://doi.org/10.2217/pgs-2019-0124

9. Guo C, Kuang Y, Zhou H, Yuan H, Pei Q, Li J, et al. Genotype-guided dosing of warfarin in Chinese adults: a multicenter randomized clinical trial. Circ Genom Precis Med. 2020 Aug;13(4):e002602. doi: https://doi.org/10.1161/circgen.119.002602

10. Chumnumwat S, Yi K, Lucksiri A, Nosoongnoen W, Chindavijak B, Chulavatnatol S, et al. Comparative performance of pharmacogenetics-based warfarin dosing algorithms derived from Caucasian, Asian, and mixed races in Thai population. Cardiovasc Ther. 2018 Apr;36(2):e12315. doi: https://doi.org/10.1111/1755-5922.12315

11. Chang GSW, Tan DSY. Using pharmacogenetic testing to tailor warfarin therapy: the Singapore experience and what the future holds. Eur Cardiol. 2020 Jun 29;15:e53. doi: https://doi.org/10.15420/ecr.2019.12

12. Vogl S, Lutz RW, Schönfelder G, Lutz WK. CYP2C9 genotype versus metabolic phenotype for individual drug dosing—a correlation analysis using flurbiprofen as probe drug. PLoS One. 2015 Mar 16;10(4):e0126329. doi: https://doi.org/10.1371%2Fjournal.pone.0120403

13. Asiimwe IG, Pirmohamed M. Ethnic diversity and warfarin pharmacogenomics. Front Pharmacol. 2022 Apr 4;13:866058. doi: https://doi.org/10.3389/fphar.2022.866058

14. Rathore SS, Agarwal SK, Pande S, Singh SK, Mittal T, Mittal B. Therapeutic dosing of acenocoumarol: proposal of a population specific pharmacogenetic dosing algorithm and its validation in north Indians. PLoS One. 2012 May 22;7(5):e37844. doi: https://doi.org/10.1371/journal.pone.0037844

15. Tong HY, Borobia AM, Quintana-Díaz M, Fabra S, González-Viñolis M, Fernández-Capitán C, et al. Acenocoumarol pharmacogenetic dosing algorithm versus usual care in patients with venous thromboembolism: a randomised clinical trial. J Clin Med. 2021 Jun 30;10(13):2949. doi: https://doi.org/10.3390/jcm10132949

16. Choi JR, Kim JO, Kang DR, Yoon SA, Shin JY, Zhang XH, et al. Proposal of pharmacogenetics-based warfarin dosing algorithm in Korean patients. J Hum Genet. 2011 Apr;56(4):290–5. doi: https://doi.org/10.1038/jhg.2011.4

17. Bauer T, Bouman HJ, Werkum JW, Ford NF, ten Berg JM, Taubert D. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. BMJ. 2011 Aug 4;343:d4588. doi: https://doi.org/10.1136/bmj.d4588

18. Luo W, Luo X, Chen S, Li J, Huang X, Rao Y, et al. Chinese stroke patients with atrial fibrillation using Roberts age-adjusted warfarin loading protocol achieved good INR results within therapeutic range. Sci Rep. 2023 Oct 25;13:18230. doi: https://doi.org/10.1038/s41598-023-45379-7

19. Wang D, Yong L, Zhang Q, Chen H. Impact of CYP2C19 gene polymorphisms on warfarin dose requirement: a systematic review and meta-analysis. Pharmacogenomics. 2022 Nov;23(16):903–11. doi: https://doi.org/10.2217/pgs-2022-0106

20. Khalighi K, Cheng G, Mirabbasi S, Khalighi B, Wu Y, Fan W. Opposite impact of Methylene tetrahydrofolate reductase C677T and Methylene tetrahydrofolate reductase A1298C gene polymorphisms on systemic inflammation. J Clin Lab Anal. 2018 Jun;32(5):e22401. doi: https://doi.org/10.1002/jcla.22401

21. Li S, Zou Y, Wang X, Huang X, Sun Y, Wang Y, et al. Warfarin dosage response related pharmacogenetics in Chinese population. PLoS One. 2015 Jan 16;10(1):e0116463. doi: https://doi.org/10.1371/journal.pone.0116463

22. Pirmohamed M. Pharmacogenomics: current status and future perspectives. Nat Rev Genet. 2023 Jun;24(6):350–62. doi: https://doi.org/10.1038/s41576-022-00572-8

23. Chong K. Warfarin dosing and VKORC1/CYP2C9. [Internet]. Newark, NJ, US: Medscape [cited 2024 Apr 10]. Available from: https://emedicine.medscape.com/article/1733331-overview?form=fpf

24. Huang SW, Xiang DK, Huang L, Chen BL, An BQ, Li GF, et al. Influence of GGCX genotype on warfarin dose requirements in Chinese patients. Thromb Res. 2011 Feb;127(2):131–4. doi: https://doi.org/10.1016/j.thromres.2010.10.027

25. Wang D, Wu H, Dong M, Zhang Q, Zhao A, Zhao X, et al. Clinical significance of the series of CYP2C9*non3 variants, an unignorable predictor of warfarin sensitivity in Chinese population. Front Cardiovasc Med. 2022 Nov 24;9:1052521. doi: https://doi.org/10.3389/fcvm.2022.1052521

26. Wang D, Wu H, Zhang Q, Zhou X, An Y, Zhap A, et al. Optimisation of warfarin-dosing algorithms for Han Chinese patients with CYP2C9*13 variants. Eur J Clin Pharmacol. 2023 Oct;79(10):1315–20. doi: https://doi.org/10.1007/s00228-023-03540-1

27. Zhu Y, Swanson KM, Rojas RL, Wang Z, St Sauver JL, Visscher SL, et al. Systematic review of the evidence on the cost-effectiveness of pharmacogenomics-guided treatment for cardiovascular diseases. Genet Med. 2020 Mar;22(3):475–86. doi: https://doi.org/10.1038/s41436-019-0667-y

28. Kubo K, Ohara M, Tachikawa M, Cavallari LH, Lee MTM, Wen MS, et al. Population differences in S-warfarin pharmacokinetics among African Americans, Asians and whites: their influence on pharmacogenetic dosing algorithms. Pharmacogenomics J. 2017 Dec;17(6):494–500. doi: https://doi.org/10.1038/tpj.2016.57

29. Al-Mahayri ZN, Khasawneh LQ, Alqasrawi MN, Altoum SM, Jamil G, Badawi S, et al. Pharmacogenomics implementation in cardiovascular disease in a highly diverse population: initial findings and lessons learned from a pilot study in United Arab Emirates. Hum Genomics. 2022 Sep 25;16(1):42. doi: https://doi.org/10.1186/s40246-022-00417-9

30. de Lara DV, de Melo DO, Araújo Silva LC, Gonçalves TS, Júnior Lima Santos PC. Pharmacogenetics of clopidogrel and warfarin in the treatment of cardiovascular diseases: an overview of reviews. Pharmacogenomics. 2022 May;23(7):443–52. doi: https://doi.org/10.2217/pgs-2021-0158

31. Cai X, Chen J, Chen M, Xia X, Fang G, Zhang J. Application of a warfarin dosing calculator to guide individualized dosing versus empirical adjustment after fixed dosing: a pilot study. Front Pharmacol. 2023 Aug 17;14:1235331. doi: https://doi.org/10.3389/fphar.2023.1235331

32. Falkenhagen U, Knöchel J, Kloft C, Huisinga W. Deriving mechanism-based pharmacodynamic models by reducing quantitative systems pharmacology models: an application to warfarin. CPT Pharmacometrics Syst Pharmacol. 2023 Apr;12(4):432–43. doi: https://doi.org/10.1002/psp4.12903

33. Wright DFB, Duffull SB. A Bayesian dose-individualization method for warfarin. Clin Pharmacokinet. 2013 Jan;52(1):59–68. doi: https://doi.org/10.1007/s40262-012-0017-6

34. Jiang NX, Ge JW, Xian YQ, Huang SY, Li YS. Clinical application of a new warfarin-dosing regimen based on the CYP2C9 and VKORC1 genotypes in atrial fibrillation patients. Biomed Rep. 2016 Apr;4(4):453–8. doi: https://doi.org/10.3892/br.2016.617

35. Asiimwe IG, Pirmohamed M. Drug-drug-gene interactions in cardiovascular medicine. Pharmacogenomics Pers Med. 2022 Nov 2;15:879–911. doi: https://doi.org/10.2147/pgpm.s338601

36. Zhu Y, Moriarty JP, Swanson KM, Takahashi PY, Bielinski SJ, Weinshilboum R, et al. A model-based cost-effectiveness analysis of pharmacogenomic panel testing in cardiovascular disease management: preemptive, reactive, or none? Genet Med. 2021 Mar;23(3):461–70. doi: https://doi.org/10.1038/s41436-020-00995-w

37. Kaur N, Pandey A, Shafiq N, Gupta A, Das R, Singh H, et al. Genetic and nongenetic determinants of variable warfarin dose requirements: a report from North India. Public Health Genomics. 2022 Jan;25(1–2):52–60. doi: https://doi.org/10.1159/000519462

38. Farzamikia N, Sakhinia E, Afrasiabirad A. Pharmacogenetics-based warfarin dosing in patients with cardiac valve replacement: the effects of CYP2C9 and VKORC1 gene polymorphisms. Lab Med. 2018 Feb;49(1):25–34. doi: https://doi.org/10.1093/labmed/lmx072

39. Galvez JM, Restrepo CM, Contreras NC, Alvarado C, Calderón-Ospina CA, Peña N, et al. Creating and validating a warfarin pharmacogenetic dosing algorithm for Colombian patients. Pharmacogenomics Pers Med. 2018 Oct 16;11:169–78. doi: https://doi.org/10.2147/pgpm.s170515

40. Mak M, Lam C, Pineda SJ, Lou M, Xu LY, Meeks C, et al. Pharmacogenetics of warfarin in a diverse patient population. J Cardiovasc Pharmacol Ther. 2019 Nov;24(6):521–33. doi: https://doi.org/10.1177/1074248419843530

41. Pirmohamed M, Burnside G, Eriksson N, Jorgensen AL, Toh CH, Nicholson T, et al. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med. 2013 Dec 12;369(24):2294–303. doi: https://doi.org/10.1056/nejmoa1311386

42. Baldacci A, Saguin E, Balcerac A, Mouchabac S, Ferreri F, Gaillard R, et al. Pharmacogenetic guidelines for psychotropic drugs: optimizing prescriptions in clinical practice. Pharmaceutics. 2023 Oct 27;15(11):2540. doi: https://doi.org/10.3390/pharmaceutics15112540

43. Pratt VM, Turner A, Broeckel U, Dawson DB, Gaedigk A, Lynnes TC, et al. Characterization of reference materials with an association for molecular pathology pharmacogenetics working group tier 2 status: CYP2C9, CYP2C19, VKORC1, CYP2C cluster variant, and GGCX: A GeT-RM collaborative project. J Mol Diagn. 2021 Aug;23(8):952–8. doi: https://doi.org/10.1016/j.jmoldx.2021.04.012

44. Johnson JA, Caudle KE, Gong L, Whirl-Carrillo M, Stein CM, Scott SA, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for pharmacogenetics-guided warfarin dosing: 2017 update. Clin Pharmacol Ther. 2017 Sep;102(3):397–404. doi: https://doi.org/10.1002/cpt.668

45. Fahmi AM, Elewa H, El Jilany I. Warfarin dosing strategies evolution and its progress in the era of precision medicine, a narrative review. Int J Clin Pharm. 2022 Jun;44(3):599–607. doi: https://doi.org/10.1007/s11096-022-01386-8

46. Hippman C, Nislow C. Pharmacogenomic testing: clinical evidence and implementation challenges. J Pers Med. 2019 Aug 7;9(3):40. doi: https://doi.org/10.3390/jpm9030040

47. Sridharan K, Al Banna R, Malalla Z, Husain A, Sater M, Jassim G, et al. Influence of CYP2C9, VKORC1, and CYP4F2 polymorphisms on the pharmacodynamic parameters of warfarin: a cross-sectional study. Pharmacol Rep. 2021 Oct;73(5):1405–17. doi: https://doi.org/10.1007/s43440-021-00256-w

48. Anand A, Kumar R, Gupta A, Vijayvergiya R, Mehrotra S, Lad D, et al. Development of an interview-based warfarin nomogram predicting the time spent in the therapeutic INR range: a cost-effective, and non-invasive strategy building from a cross sectional study in a low resource setting. Indian Heart J. 2022 May-Jun;74(3):245–8. doi: https://doi.org/10.1016/j.ihj.2022.03.008

49. Sun B, Ma S, Xiao F, Luo J, Liu M, Liu W, et al. Integrated analysis of clinical and genetic factors on the interindividual variation of warfarin anticoagulation efficacy in clinical practice. BMC Cardiovasc Disord. 2023 May 31;23(1):279. doi: https://doi.org/10.1186/s12872-023-03321-9

50. Stevens SM, Woller SC, Kreuziger LB, Bounameaux H, Doerschug K, Geersing GJ, et al. Executive summary: antithrombotic therapy for VTE disease: second update of the CHEST guideline and expert panel report. Chest. 2021 Dec;160(6):2247–59. doi: https://doi.org/10.1016/j.chest.2021.07.056

51. Lawal OD, Aronow HD, Hume AL, Shobayo F, Matson KL, Barbour M, et al. Venous thromboembolism, chronic liver disease and anticoagulant choice: effectiveness and safety of direct oral anticoagulants versus warfarin. Res Pract Thromb Haemost. 2024 Jan;8(1):102293. doi: https://doi.org/10.1016/j.rpth.2023.102293

Article Metrics
37 Views 34 Downloads 71 Total

Year

Month

Related Search

By author names