Frequency of two VKORC1 gene variants and its correlation with warfarin maintenance dose

Authors

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

Abstract
Warfarin is a commonly-prescribed anticoagulant used to treat and prevent thromboembolic events. The requirement for varying doses of warfarin depends on genetic and environmental components. In this study, the frequency of two single-nucleotide polymorphic variants of the vitamin K epoxide reductase complex subunit 1 (VKORC1) gene (1173 C>T (rs9934438) and 3730 G>A (rs7294)) and its correlation with warfarin maintenance doses were investigated in patients with heart valve replacement from West Azarbayejan, Iran. Blood samples were obtained from 185 patients; their genomic DNA was extracted and samples were genotyped by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) assay. To assess if the blood warfarin level is different among genotypes, we used a one-way analysis of variance (ANOVA) followed by a Tukey’s post-hoc comparison. The minor allele frequency was determined to be 54% for 1173T and 53.7% for 3730A. Patients who carried the G allele at position 3730 and T allele at position 1173 required a significantly lower daily mean warfarin dosage (P <0.001). Consideration of the VKORC1 gene polymorphism, especially at the initial stages of the therapy, can be helpful in pre-treatment dosing of warfarin, which, in turn, reduces the adverse effects resulting from inappropriate drug prescription.

Keywords


Bodin, L., Verstuyft, C., Tregouet, D.A., Robert A., Dubert L., Funck-Brentano, C., Jaillon, P., Beaune, P., Laurent-Puig P., Becquemont L. and Loriot, M.A. 2005. Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity. – Blood 106: 135-140.
D’Andrea, G., D’Ambrosio, R.L., Di Perna, P., Chetta, M., Santacroce, R., Brancaccio, V., Grandone, E. and Margaglione, M. 2005. A polymorphism in VKORC1 gene modulates oral anticoagulation with warfarin. – Blood 105: 645-649.
Kosaki, K., Yamaghishi, C., Sato, R., Semejima, H., Fuijita, H., Tamura, K., Maeyama, K., Yamagishi, H., Sugaya, A., Dodo, H., Tanigawara, Y. and Takahashi, T. 2006. 1173C>T polymorphism in VKORC1 modulates the required warfarin dose. – Pediatr. Cardiol. 27: 685-688.
Li, T., Lange, L.A., Li, X., Susswein, L., Bryant, B., Malone, R., Lange, E.M., Huang, T.Y., Stafford, D.W. and Evans, J.P. 2006. Polymorphisms in the VKORC1 gene are strongly associated with warfarin dosage requirements in patients receiving anticoagulation. – J. Med. Genet. 43: 740-744.
Oldenburg, J., Watzka, M., Rost, S. and Muller, C.R. 2007. VKORC1: molecular target of coumarins. – J. Thromb. Haemost. 5: 1-6.
Reitsma, J.B., Glas, A.S., Rutjes, A.W., Scholten, R.J., Bossuyt, P.M. and Zwinderman, A.H. 2005. Bivariate analysis of sensitivity and specificity produces informative summary measures in diagnostic reviews. – J. Clin. Epidemiol. 58: 982-990.
Rost, S., Fregin, A., Ivaskevicius, V., Conzelmann, E., Hortnagel, K., Pelz, H.J., Lappegard, K., Seifried, E., Scharrer, I., Tuddenham, E.G., Müller, C.R., Strom, T.M. and Oldenburg, J. 2004. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. – Nature 427: 537-541.
Salehifar, E., Farhadi, F., Janbabai, G.H. and Ahangar, N. 2012. Frequency of VKORC1 gene polymorphisms and its association with warfarin dose requirement in patients from mazandaran province. – J. Mazand. Univ. Med. Sci 22: 44-52.
Sconce, E.A., Khan, T.I., Daly, A.K., Wynne, H.A. and Kamali F. 2006. The impact of simvastatin on warfarin disposition and dose requirements. – JTH. 4:1422-1424.
Shen, G., Cui, W., Zhang, H., Zhou F., Huang W., Liu Q., Yang Y., Li S., Bowman G.R., Sadler J.E., Gross M.L., and Li, W. 2017. Warfarin traps human vitamin K epoxide reductase in an intermediate state during electron transfer. – Nat. Struct. Mol. Biol. 24: 69-76.
Shoeb, M. and Fang, M.C. 2013. Assessing bleeding risk in patients taking anticoagulants. – J. Thromb. Thrombolysis 35: 312-319.
Tamargo, J., Le Heuzey, J.Y. and Mabo, P. 2015. Narrow therapeutic index drugs: a clinical pharmacological consideration to flecainide. – Eur. J. Clin. Pharmacol. 71: 549-567.
Tie, J.K. and Stafford, D.W. 2016. Structural and functional insights into enzymes of the vitamin K cycle. – J. Thromb. Haemost 14: 236-247.
Wolf, C.R., Smith, G. and Smith, R.L. 2000. Science, medicine, and the future: Pharmacogenetics. – BMJ. 320: 987-990.
Witt, D.M., Clark, N.P., Kaatz, S., Schnurr, T., and Ansell, J.E. 2016. Guidance for the practical management of warfarin therapy in the treatment of venous thromboembolism. – J. Thromb. Thrombolysis 41: 187-205.
Yuan, H.Y., Chen, J.J., Lee, M.T., Wung, J.C., Chen, Y.F., Charng, M.J., Lu, M.J., Hung, C.R., Wei, C.Y., Chen, C.H., Wu, J.Y. and Chen, Y.T. 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.
Zhang, J., Chen, Z. and Chen, C. 2016. Impact of CYP2C9, VKORC1 and CYP4F2 genetic polymorphisms on maintenance warfarin dosage in Han-Chinese patients: A systematic review and meta-analysis. – Meta Gene 9: 197-209.
Volume 5, Issue 3 - Serial Number 17
Autumn 2018
Pages 237-243

  • Receive Date 08 June 2026
  • Publish Date 08 June 2026