The Effect of CYP2C9 and VKORC1 Genetic Polymorphism on Warfarin Dose Requirements in a Sample of Iraqi Patients

Document Type : Original Article


1 Assistant lecturer Department of pharmacology Faculty of Pharmacy, Al-Rafidain University College Baghdad, Iraq

2 Assistant Professor, Dept. of Pharmacology and Toxicology, College of Pharmacy, Al-Nahrain University, Baghdad, Iraq

3 Professor, Dept. of Pharmacology and Toxicology, College of Pharmacy, University of Kerbala, Kerbala, Iraq

4 Professor, Dept. of Microbiology, College of Medicine, Al-Nahrain University, Baghdad, Iraq

5 Assistant Professor, Dept. of Internal Medicine (Cardiology), College of Medicine ,Al-Nahrain University, Baghdad, Iraq


Background: Warfarin is the most widely used oral anticoagulant for the prevention and treatment of thromboembolic disorders. Because of narrow therapeutic index and various genetic and non-genetic factors that influence the disposition of the drug, its dose undergoes a great variability. The aim of this study was to determine the allelic variants of CYP2C9 and VKORC1 genes in Iraqi patients, and to investigate the contribution of genetic on warfarin dose requirements.
Methods: A cross sectional study was carried out on a sample of Iraqi patients from Baghdad city who were admitted to Ibn AL-Bitar Specialized Center for cardiac surgery. Blood samples of all patients were collected for both hematological and genetic analysis utilizing standard techniques.
Results: The frequency of CYP2C9*3 allele was 9.4% whereas that of CYP2C9*2 allele was 13.7%. The frequency of (VKORC1-1639G) allele was 58.75% and the frequency of (VKORC1-1639A) allele was 41.25%. Patients’ daily warfarin doses were administered according to their genotype.
Conclusion:It can be concluded that CYP2C9*3 and VKORC1 had significant effect on warfarin dose. New warfarin-dosing algorithm was developed based on CYP2C9*3 and VKORC1genotypes for predicting the required dose of warfarin.


  1. Keeling D, Baglin T, Tait C, Watson H, Perry D, Baglin C, et al. Guidelines on oral anticoagulation with warfarin–fourth edition. Br J Haematol 2011; 154(3):311-24.
  2. 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(7):2329-33.
  3. Wadelius M, Sörlin K, Wallerman O, Karlsson J, Yue QY, Magnusson PK, et al. Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors. Pharmacogenomics J 2004; 4(1):40-8.
  4. Dean L. Warfarin therapy and VKORC1 and CYP genotype. [cited 2019 Oct 12] Available from:
  5. Jones DR, Kim SY, Guderyon M, Yun CH, Moran JH, Miller GP. Hydroxywarfarin metabolites potently inhibit CYP2C9 metabolism of S-warfarin. Chem Res Toxicol 2010; 23(5):939-45.
  6. Schwarz UI, Stein CM. Genetic determinants of dose and clinical outcomes in patients receiving oral anticoagulants. Clin Pharmacol Ther 2006; 80(1):7-12.
  7. Wadelius M, Chen LY, Downes K, Ghori J, Hunt S, Eriksson N, et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J 2005; 5(4):262-70.
  8. Gage BF, Eby C, Johnson JA, Deych E, Rieder MJ, Ridker PM, et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther 2008; 84(3):326-31.
  9. Hamajima N, Saito T, Matsuo K, Kozaki K, Takahashi T, Tajima K. Polymerase chain reaction with confronting two-pair primers for polymorphism genotyping. Jpn J Cancer Res 2000; 91:865-68.
  10. Hamajima N, Katsuda N, Matsuo K, Saito T, Ito LS, Ando M,et al. Smoking habit andinterleukin lB C-31T polymorphism. J Epidemiol 2001; 11(3):120-5.
  11. Breslauer KJ, Frank R, Blöcker H, Marky LA. Predicting DNA duplex stability from the base sequence. Proc Natl AcadSci USA 1986; 86(11):3746-50.
  12. D'Andrea G, D'Ambrosio RL, Di Perna P, 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(2):645-9.
  13. 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; 4(4):453-8.
  14. Choi JR, Kim JO, Kang DR, Yoon SA, Shin JY, Zhang X, et al. Proposal of pharmacogenetics-based warfarin dosing algorithm in Korean patients. J Hum Genet 2011; 56(4):290-5.
  15. Shalia KK, Doshi SM, Parikh S, Pawar PP, Divekar SS, Varma SP, et al. Prevalence of VKORC1 and CYP2C9 gene polymorphisms in Indian population and its effect on warfarin response. J Assoc Physicians India 2012; 60:34-8.
  16. Kimura R, Miyashita K, Kokubo Y, Akaiwa Y, Otsubo R, Nagatsuka K, et al. Genotypes of vitamin K epoxide reductase, gamma-glutamyl carboxylase and cytochrome P450 2C9 as determinants of daily warfarin dose in Japanese patients. Thromb Res 2007; 120(2):181-6.
  17. Wang TL, Li HL, Tjong WY, Chen QS, Wu GS, Zhu HT, et al. Genetic factors contribute to patient-specific warfarin dose for Han Chinese. Clin Chim Acta 2008; 396(1):76-9.