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VKORC1 and CYP2C9 polymorphisms are associated with warfarin dose requirements in Turkish patients

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objectives

The objective of this study was to determine the quantitative influence of vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP 2C9) polymorphisms on warfarin dose requirements in Turkish patients.

Methods

A total of 205 patients taking warfarin for >2 months were enrolled in the study. Deoxyribonucleic acid (DNA) samples from these patients were genotyped for polymorphisms in VKORC1 and CYP2C9 genes. A linear regression analysis was used to determine the independent effects of genetic and non-genetic factors on mean warfarin dose requirements.

Results

The VKORC1 promoter polymorphism (3673 G>A) was associated with differences in weekly mean varfarin dose: for GG genotype the dose was 43.18 mg/week, for GA genotype 33.78 mg/week and for AA genoype 25.83 mg/week (P < 0.0001). Patients who carried VKORC1 and CYP2C9 variants needed a 40% lower mean weekly warfarin dose compared to wild types. Variables associated with lower warfarin dose requirements were VKORC1 3673 AA or GA genotype (both P < 0.0001), one or two CYP2C9 variant alleles (both P < 0.0001), increasing age (P < 0.0001) and non-indication of venous thromboembolism for warfarin therapy (P = 0.002).

Conclusion

Polymorphisms in VKORC1 and CYP2C9 genes were important determinants of warfarin dose requirements in Turkish patients.

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References

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

    Article  PubMed  CAS  Google Scholar 

  2. Van den Besselaar AM (1985) Standardization of the prothrombin time in oral anticoagulant control. Haemostasis 15:271–277

    PubMed  Google Scholar 

  3. Landefeld C, Beyth R (1993) Anticoagulant-related bleeding: clinical epidemiology, prediction and prevention. Am J Med 95:315–328

    Article  PubMed  CAS  Google Scholar 

  4. Gage BF, Eby CS (2003) Pharmacogenetics and anticoagulant therapy. J Thromb Thrombolysis 16:73–78

    Article  PubMed  CAS  Google Scholar 

  5. Kamali F, Khan TI, King BP, Frearson R, Kesteven P, Wood P et al (2004) Contribution of age, body size, and CYP2C9 genotype to anticoagulant response to warfarin. Clin Pharmacol Ther 75:204–212

    Article  PubMed  CAS  Google Scholar 

  6. Aquilante CL, Langaee T, Lopez LM, Yarandi HN, Tromberg JS, Mohuczy D, Gaston KL et al (2006) Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements. Clin Pharmacol Ther 79:291–302

    Article  PubMed  CAS  Google Scholar 

  7. Rettie AE, Korzekwa KR, Kunze KL, Lawrence RF, Eddy AC, Aoyama T et al (1992) Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions. Chem Res Toxicol 5:54–59

    Article  PubMed  CAS  Google Scholar 

  8. Takahashi H, Echizen H (2001) Pharmacogenetics of warfarin elimination and its clinical implications. Clin Pharmacokinet 40:587–603

    Article  PubMed  CAS  Google Scholar 

  9. Daly AK, King BP (2003) Pharmacogenetics of oral anticoagulants. Pharmacogenetics 13:247–252

    Article  PubMed  CAS  Google Scholar 

  10. Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW (2004) Identification of the gene for vitamin K epoxide reductase. Nature 427:541–544

    Article  PubMed  CAS  Google Scholar 

  11. Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hörtnagel K, Pelz HJ et al (2004) Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 427:537–541

    Article  PubMed  CAS  Google Scholar 

  12. D’Andrea G, D’Ambrosio RL, Di Perna P, Chetta M, Santacroce R, Brancaccio V et al (2005) A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood 105:645–649

    Article  PubMed  CAS  Google Scholar 

  13. Wadelius M, Chen LY, Downes K, Ghori J, Hunt S, Eriksson N et al (2005) Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J 5:262–270

    Article  PubMed  CAS  Google Scholar 

  14. Yuan HY, Chen JJ, Lee MT, Wung JC, Chen YF, Charng MJ et al (2005) A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet 14:1745–1751

    Article  PubMed  CAS  Google Scholar 

  15. Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, Mcleod HL et al (2005) Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 352:2285–2293

    Article  PubMed  CAS  Google Scholar 

  16. Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, King BP et al (2005) The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 106:2329–2333

    Article  PubMed  CAS  Google Scholar 

  17. Schalekamp T, Brasse BP, Roijers JF, Chahid Y, van Geest Daalderop JH et al (2006) VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects overanticoagulation. Clin Pharmacol Ther 80:13–22

    Article  PubMed  CAS  Google Scholar 

  18. Carlquist JF, Horne BD, Muhlestein JB, Lappé DL, Whiting BM, Kolek MJ et al (2006) Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study. J Thromb Thrombolysis 22(3):191–197

    Article  PubMed  CAS  Google Scholar 

  19. Schelleman H, Chen Z, Kealey C, Whitehead AS, Christie J, Price M et al (2007) Warfarin response and vitamin K epoxide reductase complex 1 in African Americans and Caucasians. Clin Pharmacol Ther 81(5):742–747

    Article  PubMed  CAS  Google Scholar 

  20. Limdi NA, Goldstein JA, Blaisdell JA, Beasley TM, Rivers CA, Acton RT (2007) Influence of CYP2C9 genotype on warfarin dose among African–Americans and European–Americans. Pers Med 4:157–169

    Article  CAS  Google Scholar 

  21. Aynacioğlu AS, Brockmöller J, Bauer S, Sachse C, Guzelbey P, Ongen Z et al (1999) Frequency of cytochrome P450 CYP2C9 variants in Turkish population and functional relevance for phenytoin. Br J Clin Pharmacol 48:409–415

    Article  PubMed  Google Scholar 

  22. Dericioglu N, Babaoglu MO, Saygi S, Bozkurt A, Yasar U (2004) Warfarin resistance with poor CYP2C9 activity and CYP2C9*1*2 genotype. Ann Pharmacother 38:899

    PubMed  Google Scholar 

  23. Yasar U, Oscarson M, Eliasson E, Sjöqvist F (2000) Mutations of the CYP2C9 gene and the response to warfarin. Surgery 128:281–285

    Article  Google Scholar 

  24. Aquilante CL, Lobmeyer MT, Langaee TY, Johnson JA (2004) Comparison of cytochrome P450 2C9 genotyping methods and implications for the clinical laboratory. Pharmacotherapy 24:720–726

    Article  PubMed  CAS  Google Scholar 

  25. Langaee TY, Ronaghi M (2005) Genetic variation analyses by pyrosequencing. Mutat Res 573:96–102

    PubMed  CAS  Google Scholar 

  26. Anderson JL, Horne BD, Stevens SM, Grove AS, Barton S, Nicholas ZP et al (2007) Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 116:2563–2570

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by a grant from the Istanbul University, Turkey, and the University of Florida Center for Pharmacogenomics. The authors would like to thank Lynda Stauffer at the University of Florida Center for Pharmacogenomics for her laboratory assistance in genotyping.

Conflict of interest

None declared.

Author information

Authors and Affiliations

  1. University of Istanbul, Istanbul, Turkey

    G. Oner Ozgon, N. Buyru, T. Ulutin, A. C. Hatemi, A. Siva & S. Saip

  2. Department of Pharmacy Practice and Center for Pharmacogenomics, University of Florida College of Pharmacy, Gainesville, FL, USA

    T. Y. Langaee, H. Feng & J. A. Johnson

  3. Department of Pharmacy Practice, University of Florida College of Pharmacy, P.O. Box 100486, Gainesville, FL, 32610, USA

    J. A. Johnson

Authors
  1. G. Oner Ozgon
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  2. T. Y. Langaee
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  3. H. Feng
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  4. N. Buyru
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  5. T. Ulutin
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  6. A. C. Hatemi
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  7. A. Siva
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  8. S. Saip
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  9. J. A. Johnson
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Corresponding author

Correspondence to J. A. Johnson.

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Oner Ozgon, G., Langaee, T.Y., Feng, H. et al. VKORC1 and CYP2C9 polymorphisms are associated with warfarin dose requirements in Turkish patients. Eur J Clin Pharmacol 64, 889–894 (2008). https://doi.org/10.1007/s00228-008-0507-5

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  • DOI: https://doi.org/10.1007/s00228-008-0507-5

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