Combined effect of CYP2C9 and VKORC1 polymorphisms on warfarin maintenance dose in Omani patients


Excepting host genetic factors, other influences on the pharmacokinetic and pharmacodynamic behavior of warfarin are subject to variations during the treatment despite attempts to stabilize the INR. In 214 Omani patients on warfarin therapy, we evaluated the extent of influence of known genetic predictors of warfarin dose variability, namely CYP2C9, CYP4F2 and VKORC1 gene polymorphisms in a genetically heterogeneous patient population. When patients were stratified according to their daily warfarin maintenance dose (to maintain INR between 2 and 3) into “low dose” (sensitive), “medium dose” (intermediate) and “high dose” (resistance) groups, overall, seven patients with three or four mutant alleles fell in the sensitive group and consequently 25% (7 out of 28) of at risk patients for over anticoagulation can be recognized by prospective pharmacogenetic testing in this patient population. Pre-prescription genotyping of these loci prior to therapy initiation will therefore benefit a small fraction of this population.

Share and Cite:

Pathare, A. , Alkindi, S. , Zadjali, S. , Misquith, R. , Wasim, F. , Berbar, T. , Paldi, A. and Krishnamoorthy, R. (2012) Combined effect of CYP2C9 and VKORC1 polymorphisms on warfarin maintenance dose in Omani patients. Open Journal of Genetics, 2, 184-189. doi: 10.4236/ojgen.2012.24024.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Guyatt, G.H., Akl, E.A., Crowther, M., Gutterman, D. and Schuünemann, H.J. (2012) Executive summary: Antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest, 141, 7S-47S. doi:10.1378/chest.1412S3
[2] Kovacs, M.J., Rodger, M. and Anderson, D.R., et al. (2003) Comparison of 10-mg and 5-mg warfarin initiation nomograms together with low-molecular-weight heparin for outpatient treatment of acute venous thromboembolism. A randomized, double-blind, controlled trial. Annals of Internal Medicine, 38, 714-719.
[3] Monkman, K., Lazo-Langner, A. and Kovacs, M.J. (2009) A 10 mg warfarin initiation nomogram is safe and effective in outpatients starting oral anticoagulant therapy for venous thromboembolism. Thrombosis Research, 124, 275-280. doi:10.1016/j.thromres.2008.12.001
[4] Cooper, G.M., Johnson, J.A., Langaee, T.Y., et al. (2008) A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose. Blood, 112, 1022-1027. doi:10.1182/blood-2008-01-134247
[5] Takeuchi, F., McGinnis, R., Bourgeois, S., et al. (2009) A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genetics, 5, 1-9. doi:10.1371/journal.pgen.1000433
[6] The Pharmacogenomics knowledge base [PharmGKB] home page.
[7] Pathare, A.V., Al Zadjali, S.A., Misquith. R., et al. (2012) Warfarin pharmacogenetics: Polymorphisms of the CYP2C9, CYP4F2, and VKORC1 loci in a genetically admixed Omani population. Human Biology, 84, 67-77. doi:10.3378/027.084.0103
[8] Cavallari, L.H., Langaee, T.Y., Momary, K.M., et al. (2010) Genetic and clinical predictors of warfarin dose requirements in African Americans. Clinical Pharmacology & Therapeutics, 87, 459-464. doi:10.1038/clpt.2009.223
[9] Rieder, M.J., Reiner, A.P., Gage, B.F., et al. (2005) Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. The New England Journal of Medicine, 352, 2285-2293. doi:10.1056/NEJMoa044503
[10] Geisen, C., Watzka, M., Sittinger, K., et al. (2005) VKORC1 haplotypes and their impact on the inter-individual and interethnical variability of oral anticoagulation. Journal of Thrombosis and Haemostasis, 94, 773-779.
[11] Pathare, A.V., Al Khabori, M., Alkindi, S., et al. (2012) Warfarin pharmacogenetics: Development of a dosing algorithm for Omani patients. Journal of Human Genetics, 57, 665-669. doi:10.1038/jhg.2012.94
[12] Daly, A.K. and King, B.P. (2003) Pharmacogenetics of oral anticoagulants. Pharmacogenetics, 13, 247-252. doi:10.1097/00008571-200305000-00002
[13] Holbrook, A., Schulman, S., Witt, D.M., et al. (2012) Evidence-based management of anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest, 141, e152S-e184S. doi:10.1378/chest.11-2295
[14] Orsi, F.A., Bizzacchi, J.M.A., dePaula, E.V., et al. (2010) VKORC1 V66M mutation in African Brazilian patients resistant to oral anticoagulant therapy. Thrombosis Research, 126, 206-210. doi:10.1016/j.thromres.2010.06.008
[15] Loebstein, R., Dvoskin, I., Halkin, H., et al. (2007) A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance. Blood, 109, 2477-2480. doi:10.1182/blood-2006-08-038984
[16] Harrington, D.J., Underwood, S., Morse, C., Shearer, M.J., Tuddenham, E.G. and Mumford, A.D. (2005) Pharmacodynamic resistance to warfarin associated with Val66Met Substitution in Vitamin K epoxide reductase complex 1. Thrombosis & Haemostasis, 93, 23-26.
[17] Vecsler, M., Loebstein, R., Almog, S., et al. (2006) Combined genetic profiles of components and regulators of the vitamin K-dependent gamma-carboxylation system affect individual sensitivity to warfarin. Journal of Thrombosis and Haemostasis, 95, 205-211.
[18] Herman, D., Peternel, P., Stegnar, M., Breskvar, K. and Dolzan, V., (2006) The influence of sequence variations in factor VII, gammaglutamyl carboxylase and vitamin K epoxide reductase complex genes on warfarin dose requirement. Journal of Thrombosis and Haemostasis, 95, 782-787.
[19] Rost, S., Fregin, A., Ivaskevicius, V., et al. (2004) Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature, 427, 537-541. doi:10.1038/nature02214
[20] Anderson, J.L., Horne, B.D., Stevens, S.M., et al. (2012) A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-II). Circulation, 125, 1997-2005. doi:10.1161/CIRCULATIONAHA.111.070920

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.