Frequencies of polymorphisms in genes affecting the pharmacokinetics of warfarin in the Zaporizhzhia region




The aim of the study: to establish the frequencies of polymorphisms in VKORC1, CYP2C9 and CYP4F2 genes among residents of the Zaporizhzhia region.

Materials and methods. A total of 150 persons (62 male, 88 female) with a median age of 46 years (26; 58) undergoing preventive examination at the Medical Educational and Scientific Center “University Clinic” of Zaporizhzhia State Medical University (ZSMU). The CYP2C9, CYP4F2, VKORC1 genes polymorphisms in atrial fibrillation patients were determined in the Department of Molecular Genetic Studies of the ZSMU Medical Laboratory Center. Amplification of DNA fragments containing polymorphic regions was performed using multiplex real time polymerase chain reaction with Warfarin Pharmacogenetics kits (LLC NPO DNA Technology) in a CFX-96 thermocycler (BioRad) with a fluorescence detection scheme.

Results. It was determined that among Zaporizhzhia region residents, the frequencies of CYP2C9*2 genotypes were: C/C – 77.3 %, C/T – 22.7 %, T/T – 0; CYP2C9*3 genotypes: A/A – 88.7 %, A/C – 10.7 %, C/C – 0.6 %; CYP4F2 genotypes: C/C – 56.0 %, C/T – 35.3 %, T/T – 8.7 %; VKORC1 genotypes: G/G – 38.0 %, G/A – 50.0 %, A/A – 12.0 %. There were no statistically significant differences in the distribution of genotype frequencies between males and females and between different age groups. The frequencies of CYP2C9, CYP4F2, VKORC1 genotypes in different populations were compared. Their variability in different geographic regions was established.

Conclusions. CYP4F2 and VKORC1 genes polymorphisms are more common in the Zaporizhzhia region, while the prevalence of CYP2C9*2 and CYP2C9*3 genes polymorphisms is much lower. It is necessary to take into account the prevalence of genes polymorphisms that affect warfarin metabolism for each individual population to select its dose by pharmacogenetic testing.

Author Biographies

M. Yu. Kolesnik, Zaporizhzhiya state medical university, Ukraine

MD, PhD, DSc, Professor of the Department of Family Medicine, Therapy, Cardiology and Neurology of Faculty of Postgraduate Education

Yа. М. Mykhailovskyi, Zaporizhzhiya state medical university, Ukraine

MD, PhD-student of the Department of Fa­mi­ly Medicine, Therapy, Cardiology and Neurology of Faculty of Postgraduate Education


Abdullah-Koolmees, H., van Keulen, A. M., Nijenhuis, M., & Deneer, V. (2021). Pharmacogenetics Guidelines: Overview and Comparison of the DPWG, CPIC, CPNDS, and RNPGx Guidelines. Frontiers in Pharmacology, 11, Article 595219.

Francis Lam, Y. W., & Scott, Stuart A. (Eds.). (2019). Pharmacogenomics. Challenges and Opportunities in Therapeutic Implementation (2nd ed.). Academic Press.

Picard, N., Boyer, J. C., Etienne-Grimaldi, M. C., Barin-Le Guellec, C., Thomas, F., Loriot, M. A., & French National Network of Pharmacogenetics (RNPGx). (2017). Pharmacogenetics-based personalized therapy: Levels of evidence and recommendations from the French Network of Pharmacogenetics (RNPGx). Therapie, 72(2), 185-192.

Sychev, D. A. (2011). Rekomendatsii po primeneniyu farmakogeneticheskogo testirovaniya v klinicheskoi praktike [Recommendations for the use of pharmacogenetic testing in clinical practice]. Kachestvennaya Klinicheskaya Praktika, (1), 3-10. [in Russian].

Graham, D. J., Baro, E., Zhang, R., Liao, J., Wernecke, M., Reichman, M. E., Hu, M., Illoh, O., Wei, Y., Goulding, M. R., Chillarige, Y., Southworth, M. R., MaCurdy, T. E., & Kelman, J. A. (2019). Comparative Stroke, Bleeding, and Mortality Risks in Older Medicare Patients Treated with Oral Anticoagulants for Nonvalvular Atrial Fibrillation. The American Journal of Medicine, 132(5), 596-604.e11.

Johnson, J. A., Caudle, K. E., Gong, L., Whirl-Carrillo, M., Stein, C. M., Scott, S. A., Lee, M. T., Gage, B. F., Kimmel, S. E., Perera, M. A., Anderson, J. L., Pirmohamed, M., Klein, T. E., Limdi, N. A., Cavallari, L. H., & Wadelius, M. (2017). Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update. Clinical Pharmacology & Therapeutics, 102(3), 397-404.

Sridharan, K., & Sivaramakrishnan, G. (2021). A network meta-analysis of CYP2C9, CYP2C9 with VKORC1 and CYP2C9 with VKORC1 and CYP4F2 genotype-based warfarin dosing strategies compared to traditional. Journal of Clinical Pharmacy and Therapeutics, 46(3), 640-648.

Sun, X., Yu, W. Y., Ma, W. L., Huang, L. H., & Yang, G. P. (2016). Impact of the CYP4F2 gene polymorphisms on the warfarin maintenance dose: A systematic review and meta-analysis. Biomedical Reports, 4(4), 498-506.

Asiimwe, I. G., Zhang, E. J., Osanlou, R., Jorgensen, A. L., & Pirmohamed, M. (2021). Warfarin dosing algorithms: A systematic review. British Journal of Clinical Pharmacology, 87(4), 1717-1729.

Levkovich, N. M., & Gorovenko, N. G. (2013) Chastota rozpovsiudzhennia alelnykh variantiv *2 i *3 hena CYP2C9 u naselennia Ukrainy [Allele frequency distribution of CYP2C9 gene in Ukrainian population] Odeskyi medychnyi zhurnal, (2), 23-28. [in Ukrainian].

Ross, K. A., Bigham, A. W., Edwards, M., Gozdzik, A., Suarez-Kurtz, G., & Parra, E. J. (2010). Worldwide allele frequency distribution of four polymorphisms associated with warfarin dose requirements. Journal of Human Genetics, 55(9), 582-589.

Maliarchuk, I. V., Gorovenko, N. G., Krykunov, А. О., & Babochkina, A. R. (2014). Klinichne znachennia polimorfnoho varianta G1639A hena VKORC1 v indyvidualizatsii terapii varfarynom [The clinical significance of G1639A polymorphic variants of VKORC1 gene for individualized therapy with warfarin]. Ukrainskyi kardiolohichnyi zhurnal, (2), 100-105. [in Ukrainian].

Ohara, M., Suzuki, Y., Shinohara, S., Gong, I. Y., Schmerk, C. L., Tirona, R. G., Schwarz, U. I., Wen, M. S., Lee, M., Mihara, K., Nutescu, E. A., Perera, M. A., Cavallari, L. H., Kim, R. B., & Takahashi, H. (2019). Differences in Warfarin Pharmacodynamics and Predictors of Response Among Three Racial Populations. Clinical Pharmacokinetics, 58(8), 1077-1089.

Buzoianu, A. D., Trifa, A. P., Mureşanu, D. F., & Crişan, S. (2012). Analysis of CYP2C9*2, CYP2C9*3 and VKORC1 -1639 G>A polymorphisms in a population from South-Eastern Europe. Journal of Cellular and Molecular Medicine, 16(12), 2919-2924.

Cavallari, L. H., Momary, K. M., Patel, S. R., Shapiro, N. L., Nutescu, E., & Viana, M. A. (2011). Pharmacogenomics of warfarin dose requirements in Hispanics. Blood Cells, Molecules, and Diseases, 46(2), 147-150.

Kimura, R., Miyashita, K., Kokubo, Y., Akaiwa, Y., Otsubo, R., Nagatsuka, K., Otsuki, T., Okayama, A., Minematsu, K., Naritomi, H., Honda, S., Tomoike, H., & Miyata, T. (2007). Genotypes of vitamin K epoxide reductase, gamma-glutamyl carboxylase, and cytochrome P450 2C9 as determinants of daily warfarin dose in Japanese patients. Thrombosis Research, 120(2), 181-186.

Bedewy, A., Sheweita, S. A., Mostafa, M. H., & Kandil, L. S. (2018). The Influence of CYP2C9 and VKORC1 Gene Polymorphisms on the Response to Warfarin in Egyptians. Indian Journal of Hematology and Blood Transfusion, 34(2), 328-336.

Harikrishnan, S., Koshy, L., Subramanian, R., Sanjay, G., Vineeth, C. P., Nair, A. J., Nair, G. M., & Sudhakaran, P. R. (2018). Value of VKORC1 (-1639G>A) rs9923231 genotyping in predicting warfarin dose: A replication study in South Indian population. Indian Heart Journal, 70(Suppl. 3), S110-S115.

EMBL-EBI. (n.d.). rs2108622. SNP.;r=19:15879121-15880121;v=rs2108622;vdb=variation;vf=202396216




How to Cite

Kolesnik, M. Y. ., & Mykhailovskyi Y. М. (2021). Frequencies of polymorphisms in genes affecting the pharmacokinetics of warfarin in the Zaporizhzhia region. Zaporozhye Medical Journal, 23(4), 476–479.



Original research