The Contribution of VKORC1 and CYP2C9 Genetic Polymorphisms and Patients’ Demographic Characteristics with Warfarin Maintenance Doses: A Suggested Warfarin Dosing Algorithm

Document Type : Research article


1 Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.

2 Department of Pharmacology, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran

3 Department of Cardiovascular Surgery, Seyyed-al-Shohada Heart Center, Urmia University of Medical Sciences, Urmia, Iran.


The requirement of varying doses of warfarin for different individuals can be explained by environmental and genetic factors. We evaluated the frequency of vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) variants together with patientdemographic characteristics and investigated their association with warfarin dose requirement with the objective to suggest a warfarin dosing algorithm. In this study, 185 patients with heart valve replacement from West Azerbaijan, Iran were genotyped for VKORC1 (-1639 G>A) and CYP2C9 (*2 and *3 alleles) by PCR-RFLP. Multiple linear regression was performed to create a new warfarin dosing algorithm. The frequency of variants in studied subjects was 12% for CYP2C9 *2, 25.8% for CYP2C9 *3, and 60% for -1639A. The patients who carried the A allele at position -1639 VKORC1 and the variants CYP2C9 *2 and *3 required a significantly lower daily mean warfarin dosage (P = 0.001). Statistical analysis also indicated a significant relationship between the daily maintenance dose of warfarin with age and blood pressure among the studied patients’ cohort (P < 0.001). This study showed that in the heart valve replacement patients considering VKORC1 and CYP2C9 polymorphisms beside demographic characteristics such as age will be helpful in pre-treatment dosing of warfarin which in turn reduces the complications associated with inappropriate warfarin dosing.

Graphical Abstract

The Contribution of  VKORC1 and CYP2C9 Genetic Polymorphisms and Patients’ Demographic Characteristics with Warfarin Maintenance Doses: A Suggested Warfarin Dosing Algorithm


(1) Leiria TLL, Lopes RD, Williams JB, Katz JN, Kalil RAK and Alexander JH. Antithrombotic therapies in patients with prosthetic heart valves: guidelines translated for the clinician. J. Thromb. Thrombolysis. (2011) 31:514–22. 
(2) Kimmel SE. Warfarin therapy: in need of improvement after all these years. Expert. Opin. Pharmacother. (2008)  9:677–86.
(3) Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, King BP, Wood P, Kesteven P, Daly AK and Kamali F. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood. (2005) 106:2329–2333.
(4) Carlquist JF, Horne BD, Muhlestein JB, Lappé DL, Whiting BM, Kolek MJ, Clarke JL, James BC and Anderson JL. 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. (2006) 22:191-7.
(5) Yildirim E, Erol K and Birdane A. Warfarin dose requirement in Turkish patients: The influences of patient characteristics and polymorphisms in CYP2C9, VKORC1 and factor VII. Hippokratia. (2014) 18: 319–327.
(6) Bodin L, Horellou MH, Flaujac C, Loriot MA and Samama MM. A vitamin K epoxide reductase complex subunit-1 (VKORC1) mutation in a patient with vitamin K antagonist resistance. J. Thromb. Haemost. (2005) 3: 1533–5.
(7) Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hortnagel K, Pelz HJ, Lappegard K, Seifried E, Scharrer I, Tuddenham EG, Müller CR, Strom TM and Oldenburg, J. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature. (2004) 427:537–41.
(8) Yuan HY, Chen JJ, Lee MTM, Wung JC, Chen YF, Charng MJ, Lu MJ, Hung CR, Wei CY, Chen CH, Wu JY and Chen YT. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum. Mol. Genet. (2005) 14:1745–51.
(9) Gong IY, Schwarz UI, Crown N, Dresser GK, Lazo-Langner A, Zou G, Roden DM, Stein CM, Rodger M, Wells PS, Kim RB and Tirona RG. Clinical and genetic determinants of warfarin pharmacokinetics and pharmacodynamics during treatment initiation. PLoS One. (2011) 6:e27808.
(10) Villagra D, Duconge J, Windemuth A, Cadilla CL, Kocherla M, Gorowski K, Bogaard K, Renta JY, Cruz IA, Mirabal S, Seip RL and Ruaño G. CYP2C9 and VKORC1 genotypes in Puerto Ricans: A case for admixture-matching in clinical pharmacogenetic studies. Clin. Chim. Acta. (2010) 411:1306–11.
(11) Lane S, Al-Zubiedi S, Hatch E, Matthews I, Jorgensen AL, Deloukas P, Daly AK, Park BK, Aarons L, Ogungbenro K, Kamali F, Hughes D and Pirmohamed M. . The population pharmacokinetics of R- and S-warfarin: effect of genetic and clinical factors. Br. J. Clin. Pharmacol. (2012) 73:66-76.
(12) Rettie AE and Tai GY. The pharmacogenomics of warfarin: Closing in on personalized medicine. Mol. Interv. (2006) 6:223–226.
(13) Yasmeen F, Ghafoor MB, Khalid AW, Latif W, Mohsin. S and Khaliq S. Analysis of CYP2C9 polymorphisms (*2 and *3) in warfarin therapy patients in Pakistan. Association of CYP2C9 polymorphisms (*2 and*3). with warfarin dose, age, PT and INR. J. Thromb. Thrombolysis. (2015) 40: 218-24.
(14) Poopak B, Rabieipoor S, Safari N, Naraghi E, Sheikhsofla F and Khosravipoor G. Identification of CYP2C9 and VKORC1 polymorphisms in Iranian patients who are under warfarin therapy. Int. J. Hematol. stem cell Res. (2015) 9:185–92.
(15) Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M and Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition) Chest. (2008) 133(6 suppl):160S–198S.
(16) Daly AK, King BP and Leathart JB. Genotyping for cytochrome P450 polymorphisms. Methods Mol Biol. (2006) 320:193-207.
(17) Askari B, Khaleqsefat E, Khalafkhani D, Khalaj-Kondori M, Khademvatan K and Soraya H. Study on a novel polymorphism in the VKORC1 promoter region using bioinformatic tools and warfarin dosing data. Thromb. Res. (2017) 158:76-78.
(18) Zhu Y, Shennan M, Reynolds KK, Johnson NA, Herrnberger MR, Valdes R Jr and Linder MW. Estimation of warfarin maintenance dose based on VKORC1 (-1639 G> A) and CYP2C9 genotypes. Clin. Chem. (2007) 53:1199–205.
(19) Öner Özgon G, Langaee TY, Feng H, Buyru N, Ulutin T, Hatemi AC and Siva A, Saip S, Johnson JA. VKORC1 and CYP2C9 polymorphisms are associated with warfarin dose requirements in Turkish patients. Eur. J. Clin. Pharmacol. (2008) 64:889–94.
(20) Liang R, Li L, Li C, Gao Y, Liu W, Hu D and Sun Y. Impact of CYP2C9*3, VKORC1-1639, CYP4F2 rs2108622 genetic polymorphism and clinical factors on warfarin maintenance dose in Han-Chinese patients. J. Thromb. Thrombolysis. (2012) 34:120–5.
(21) D’Andrea G, D’Ambrosio RL, Di Perna P, Chetta M, Santacroce R, Brancaccio V, Grandone E and Margaglione M. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood. (2005) 105:645–9.
(22) Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, Blough DK, Thummel KE, Veenstra DL and Rettie AE. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N. Engl. J. Med. (2005) 352:2285–93.
(23) Lam MPS and Cheung BMY. The pharmacogenetics of the response to warfarin in Chinese. Br. J. Clin. Pharmacol. (2012) 73:340–7.
(24) Aithal GP, Day CP, Kesteven PJ and Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet. (1999) 353:717-9.
(25) Razavi FEZarban AHajipoor F and Naseri M. The allele frequency of CYP2C9 and VKORC1 in the Southern Khorasan population. Res. Pharm. Sci. (2017) 12:211-221.
(26) Ozer N, Cam N, Tangurek B, Ozer S, Uyarel H, Oz D, Guney MR and Ciloglu F. The impact of. CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements in an adult Turkish population. Heart Vessels. (2010) 25: 155-162.
(27) Fung E, Patsopoulos NA, Belknap SM, O'Rourke DJ, Robb JF, Anderson JL, Shworak NW and Moore JH. Effect of genetic variants, especially CYP2C9 and VKORC1, on the pharmacology of warfarin. Semin. Thromb. Hemost. (2012) 38:893–904.
(28) Teh LK, Langmia IM, Fazleen Haslinda MH, Ngow HA, Roziah MJ, Harun R, Zakaria ZA and Salleh MZ. Clinical relevance of VKORC1 (G-1639A and C1173T) and CYP2C9*3 among patients on warfarin. J. Clin. Pharm. Ther. (2012) 37: 232–6.
(29) Park SM, Lee J-K, Chun S Il, Lee HI, Kwon SU, Kang DW and Kim JS. VKORC1 and CYP2C9 Genotype Variations in Relation to Warfarin Dosing in Korean Stroke Patients. J. stroke. (2013) 15:115–21.
(30) Baniasadi S, Beizaee S, Kazemi B, Behzadnia N, Shafaghi B, Bandehpour M and Fahimi F. Novel VKORC1 mutations associated with warfarin sensitivity. Cardiovascular Therapeutics. (2011) 29: e1–e5.