Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Association between VKORC1 gene polymorphism and warfarin dose requirement and frequency of VKORC1 gene polymorphism in patients from Kerman province

The Pharmacogenomics Journal volume 20, pages 574–578 (2020)Cite this article

Subjects

Abstract

Warfarin is an anticoagulant prescribed in the treatment and prevention of thrombosis. Variation in dose requirements is different for everyone, and genetic factors have an effect on dose variation. Polymorphism of vitamin K epoxide reductase complex 1 (VKORC1) gene is identified as the main genetic factor involved in warfarin dosage requirement variations. This study aims to determine the frequency of VKORC1 polymorphism in patients using warfarin from Kerman city and investigated association between VKORC1 gene polymorphism and patient characteristics with warfarin dose requirement. A total of 112 patients taking warfarin with stable dose requirements enrolled in the study. DNA samples from these patients were genotyped for VKORC1 gene polymorphism by using the polymerase chain reaction restriction fragment length polymorphism method (PCR-RFLP) and examined associations between demographic characteristics (e.g. age, sex, smoking, etc.) and genetic factors with maintenance dose of warfarin. The most common genotype was VKORC1 GA (48.2%). genotype frequency subjects carried VKORC1 GG and AA were 39.3% and 12.5%, respectively. In addition, a significant relationship was found between VKORC1-1639G>A and the daily dose of warfarin (P = 0.011, R2 = 0.080). The frequencies of the VKORC1-1639 A alleles were significantly lower than VKORC1-1639 G alleles and required fewer warfarin dose.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Makris M, Watson HG. The management of coumarin-induced over-anticoagulation Annotation. Br J Haematol. 2001;114:271–80.

    Article  CAS  Google Scholar 

  2. Piatkov I, Rochester C, Jones T, Boyages S. Warfarin toxicity and individual variability-clinical case. Toxins. 2010;2:2584–92. https://doi.org/10.3390/toxins2112584.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cavallari LH, Perera MA. The future of warfarin pharmacogenetics in under-represented minority groups. Future Cardiol. 2012;8:563–76. https://doi.org/10.2217/fca.12.31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mazzaccara C, Conti V, Liguori R, Simeon V, Toriello M, Severini A, et al. Warfarin anticoagulant therapy: a Southern Italy pharmacogenetics-based dosing model. PLoS One. 2013;8:e71505. https://doi.org/10.1371/journal.pone.0071505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mahajan P, Meyer KS, Wall GC, Price HJ. Clinical applications of pharmacogenomics guided warfarin dosing. Int J Clin Pharm. 2011;33:10–9. https://doi.org/10.1007/s11096-011-9486-1.

    Article  CAS  PubMed  Google Scholar 

  6. Burmester JK, Berg RL, Glurich I, Yale SH, Schmelzer JR, Caldwell MD. Absence of novel CYP4F2 and VKORC1 coding region DNA variants in patients requiring high warfarin doses. Clin Med Res. 2011;9:119–24. https://doi.org/10.3121/cmr.2011.951.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. You JH. Pharmacoeconomic evaluation of warfarin pharmacogenomics. Expert Opin Pharmacother. 2011;12:435–41. https://doi.org/10.1517/14656566.2011.521153.

    Article  CAS  PubMed  Google Scholar 

  8. Wu AH. Drug metabolizing enzyme activities versus genetic variances for drug of clinical pharmacogenomic relevance. Clin Proteom. 2011;8:12. https://doi.org/10.1186/1559-0275-8-12.

    Article  Google Scholar 

  9. Lane S, Al-Zubiedi S, Hatch E, Matthews I, Jorgensen AL, Deloukas P, et al. The population pharmacokinetics of R- and S-warfarin: effect of genetic and clinical factors. Br J Clin Pharmacol. 2012;73:66–76. https://doi.org/10.1111/j.1365-2125.2011.04051.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Pavani A, Naushad SM, Rupasree Y, Kumar TR, Malempati AR, Pinjala RK, et al. Optimization of warfarin dose by population-specific pharmacogenomic algorithm. Pharmacogenom J. 2012;12:306–11. https://doi.org/10.1038/tpj.2011.4.

    Article  CAS  Google Scholar 

  11. Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW. Identification of the gene for vitamin K epoxide reductase. Nature. 2004;427:541–4. https://doi.org/10.1038/nature02254.

    Article  CAS  PubMed  Google Scholar 

  12. Hirsh J, Bates SM. Clinical trials that have influenced the treatment of venous thromboembolism: a historical perspective. Ann Intern Med. 2001;134:409–17.

    Article  CAS  Google Scholar 

  13. Hirsh J, Dalen J, Anderson DR, Poller L, Bussey H, Ansell J, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest. 2001;119:8s–21s.

    Article  CAS  Google Scholar 

  14. Kamali F, Wynne H. Pharmacogenetics of warfarin. Annu Rev Med. 2010;61:63–75. https://doi.org/10.1146/annurev.med.070808.170037.

    Article  CAS  PubMed  Google Scholar 

  15. Kabalak PA, Savas I, Akar N, Demir N, Egin Y. Frequency of vitamin K oxidoreductase complex subunit-1 (VKORC1) polymorphisms and warfarin dose management in patients with venous thromboembolism. Pharmacogenom J. 2018;18:646–51. https://doi.org/10.1038/s41397-018-0037-1.

    Article  CAS  Google Scholar 

  16. Poopak B, Rabieipoor S, Safari N, Naraghi E, Sheikhsofla F, Khosravipoor G. Identification of CYP2C9 and VKORC1 polymorphisms in Iranian patients who are under warfarin therapy. Int J Hematol Oncol Stem Cell Res. 2015;9:185–92.

    PubMed  PubMed Central  Google Scholar 

  17. Alzahrani AM, Ragia G, Hanieh H, Manolopoulos VG. Genotyping of CYP2C9 and VKORC1 in the Arabic population of Al-Ahsa, Saudi Arabia. Biomed Res Int. 2013;2013:315980. https://doi.org/10.1155/2013/315980.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215.

    Article  CAS  Google Scholar 

  19. Shehab N, Sperling LS, Kegler SR, Budnitz DS. National estimates of emergency department visits for hemorrhage-related adverse events from clopidogrel plus aspirin and from warfarin. Arch Intern Med. 2010;170:1926–33. https://doi.org/10.1001/archinternmed.2010.407.

    Article  PubMed  Google Scholar 

  20. Ni X, Zhang W, Huang RS. Pharmacogenomics discovery and implementation in genome-wide association studies era. Wiley Interdiscip Rev Syst Biol Med. 2013;5:1–9. https://doi.org/10.1002/wsbm.1199.

    Article  CAS  PubMed  Google Scholar 

  21. DARILMAZ YÜCE G. Effect of genetic variations on adjusting of warfarin dose. Tuberculosis Thorax. 2014;62:236–42.

    PubMed  Google Scholar 

  22. Wen MS, Lee M, Chen JJ, Chuang HP, Lu LS, Chen CH, et al. Prospective study of warfarin dosage requirements based on CYP2C9 and VKORC1 genotypes. Clin Pharmacol Ther. 2008;84:83–9. https://doi.org/10.1038/sj.clpt.6100453.

    Article  CAS  PubMed  Google Scholar 

  23. Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, King BP, et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood. 2005;106:2329–33. https://doi.org/10.1182/blood-2005-03-1108.

    Article  CAS  PubMed  Google Scholar 

  24. Greaves M. Pharmacogenetics in the management of coumarin anticoagulant therapy: the way forward or an expensive diversion? PLoS Med. 2005;2:e342. https://doi.org/10.1371/journal.pmed.0020342.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Borgiani P, Ciccacci C, Forte V, Sirianni E, Novelli L, Bramanti P, et al. CYP4F2 genetic variant (rs2108622) significantly contributes to warfarin dosing variability in the Italian population. Pharmacogenomics. 2009;10:261–6. https://doi.org/10.2217/14622416.10.2.261.

    Article  CAS  PubMed  Google Scholar 

  26. Zambon CF, Pengo V, Padrini R, Basso D, Schiavon S, Fogar P, et al. VKORC1, CYP2C9 and CYP4F2 genetic-based algorithm for warfarin dosing: an Italian retrospective study. Pharmacogenomics. 2011;12:15–25. https://doi.org/10.2217/pgs.10.162.

    Article  CAS  PubMed  Google Scholar 

  27. D'Andrea G, D'Ambrosio RL, Perna PD, Chetta M, Santacroce R, Brancaccio V, et al. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood. 2005;105:645–9. https://doi.org/10.1182/blood-2004-06-2111.

    Article  CAS  PubMed  Google Scholar 

  28. Cini M, LEGNANI C, COSMI B, GUAZZALOCA G, VALDRE L, FRASCARO M, et al. A new warfarin dosing algorithm including VKORC1 3730 G > A polymorphism: comparison with results obtained by other published algorithms. Eur J Clin Pharmacol. 2012;68:1167–74. https://doi.org/10.1007/s00228-012-1226-5.

    Article  CAS  PubMed  Google Scholar 

  29. 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. https://doi.org/10.2217/pgs.10.49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yang L, Ge W, Yu F, Zhu H. Impact of VKORC1 gene polymorphism on interindividual and interethnic warfarin dosage requirement-a systematic review and meta analysis. Thrombosis Res. 2010;125:e159–166. https://doi.org/10.1016/j.thromres.2009.10.017.

    Article  CAS  Google Scholar 

  31. Limdi NA, Arnett DK, Goldstein JA, Beasley TM, McGwin G, Adler BK, et al. Influence of CYP2C9 and VKORC1 on warfarin dose, anticoagulation attainment and maintenance among European-Americans and African-Americans. Pharmacogenomics. 2008;9:511–26. https://doi.org/10.2217/14622416.9.5.511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Miura T, Nishinaka T, Terada T, Yonezawa K. Relationship between aging and dosage of warfarin: the current status of warfarin anticoagulant therapy for Japanese outpatients in a department of cardiovascular medicine. J Cardiol. 2009;53:355–60. https://doi.org/10.1016/j.jjcc.2008.12.003.

    Article  PubMed  Google Scholar 

  33. Khoury G, Sheikh-Taha M. Effect of age and sex on warfarin dosing. Clin Pharmacol. 2014;6:103–6. https://doi.org/10.2147/cpaa.s66776.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors appreciate Dr Dabiri, Member of Pathology Department, Afzalipour School of Medicine, Kerman University of Medical Sciences, for his help.

Author information

Authors and Affiliations

  1. Department of Microbiology, Kerman Branch, Islamic Azad University, Kerman, Iran

    Mohammad Javad Soltani Banavandi

  2. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran

    Naghmeh Satarzadeh

Authors
  1. Mohammad Javad Soltani Banavandi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naghmeh Satarzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mohammad Javad Soltani Banavandi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Soltani Banavandi, M.J., Satarzadeh, N. Association between VKORC1 gene polymorphism and warfarin dose requirement and frequency of VKORC1 gene polymorphism in patients from Kerman province. Pharmacogenomics J 20, 574–578 (2020). https://doi.org/10.1038/s41397-019-0146-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41397-019-0146-5

This article is cited by

Search

Advanced search

Quick links