PREVALENCE OF POLYMORPHISMS IN WARFARIN METABOLISM-RELATED GENES AMONG THE KAZAKH POPULATION
Objective: The study aims to perform a comparative analysis of population frequencies of minor alleles of polymorphisms in the genes CYP2C9 *2 (rs1799853), *3 (rs1057910), *5 (rs28371686), and *6 (rs9332131); CYP2C19 (rs3814637), VKORC1 (rs9934438), CYP4F2 (rs2108622), GGCX (rs11676382), as well as GWAS-associated variants related to resistance to vitamin K antagonists in an ethnically homogeneous Kazakh population, and to assess the distribution and perform a comparative analysis of metabolic phenotypes ("metabolizer types") in comparison with previously studied global populations.
Materials and Methods: The research was based on genomic analysis data from 1,900 conditionally healthy individuals of Kazakh ethnicity, obtained within the framework of the 7th Framework Programme of the European Union under Grant Agreement No. 282540.
Results: A high frequency of the minor allele of the "Asian" variant rs11676382 in the GGCX gene was identified in the Kazakh population (14.4%) compared to European, East Asian, and South Asian groups. It may indicate a potentially more pronounced impact of this polymorphism on individual warfarin dosing requirements in individuals of Kazakh ethnicity.
In the studied Kazakh group, the identified phenotypes and frequencies of metabolizers for CYP2C9 *2 (rs1799853) and *3 (rs1057910) alleles were as follows: 1/1 (80.1%), 1/3 (13.0%), 3/3 (0.25%), 1/2 (6.0%), 2/3 (0.40%), and 2/2 (0.25%). Normal metabolizers (*2 and *3 alleles) comprised 80.1%, intermediate metabolizers - 19.0%, and slow metabolizers - 0.9%.
For CYP2C9 *5 (rs28371686) and *6 (rs9332131) alleles, the phenotypes and metabolizer frequencies were: 1/1 (90.0%), 1/6 (6.7%), 1/5 (2.9%), 5/6 (0.3%), and 5/5 (0.1%). Normal metabolizers for *5 and *6 alleles accounted for 90.0%, intermediate - 9.6%, and slow - 0.4%.
Conclusion. The results provide additional pharmacogenetic database information for Central Asia, facilitating a better understanding of warfarin pharmacokinetics and pharmacodynamics for individualized warfarin dosing in patients undergoing heart surgery in Kazakhstan.
Alexandra V. Murtazaliyeva – geneticist, researcher at the Center for Education and Science in LLP "Center for Molecular Medicine", Almaty, Republic of Kazakhstan, ORCID ID 0000-0001-9156-5944, A05B1E1, 130 Ayitiyev Str., Almaty, Kazakhstan; phone: +7 (771) 799-91-00, e-mail: alexmurtazalieva@gmail.com
Galina M. Berezina – Doctor of Biological Sciences, Associate Professor, Leading Researcher, Department of Strategy and Science, Republican Medical Genetic Consultation of Joint-Stock Company “Scientific Center of Obstetrics, Gynecology and Perinatology; ORCID ID 0000-0002-5442-4461, A25D6G4, 125 Dostyk Ave., Almaty, Kazakhstan; phone: +7 (727) 300-45-62, e-mail: gberezina54@mail.ru
Gulnara S. Svyatova – Doctor of Medicine, Professor, Head of the Center for Education and Science in LLP "Center for Molecular Medicine", ORCID ID 0000-0001-5092-3143, A05B1E1, 130 Ayitiyev Str., Almaty, Kazakhstan; phone: +7 (771) 799-91-00, e-mail: gsvyatova1@mail.ru
Meruert S. Yesset – Specialist of the Laboratory in Republican Medical Genetic Consultation of Joint-Stock Company “ Scientific Center of Obstetrics, Gynecology and Perinatology”, ORCID ID 0000-0003-2906-5636, A25D6G4, 125 Dostyk Ave., Almaty, Kazakhstan; phone: +7 (727) 300-45-62, e-mail: eset_m@mail.ru
Asem T. Burabayeva – Resident in Medical Genetics in Joint-Stock Company “Scientific Center of Obstetrics, Gynecology and Perinatology”, ORCID ID 0009-0005-4527-7729, A25D6G4, 125 Dostyk Ave., Almaty, Kazakhstan; phone: +7 (727) 300-45-62, e-mail: dr.burabayeva@mail.ru
1. Здоровье населения Республики Казахстан и деятельность организаций здравоохранения в 2022 году. Статистический сборник. 2023. 361 с. URL: https://www.gov.kz/memleket/entities/dsm/documents/details/583047?lang=ru&ysclid=lw95eckbga54388976
2. Al-Eitan L.N., Almasri A.Y., Khasawneh R.H. Impact of CYP2C9 and VKORC1 Polymorphisms on Warfarin Sensitivity and Responsiveness in Jordanian Cardiovascular Patients during the Initiation Therapy. Genes (Basel). 2018. 27;9(12). P.578. doi: 10.3390/genes9120578.
3. Azarpira N., Namazi S., Hendijani F., Banan M., Darai M. Investigation of allele and genotype frequencies of CYP2C9, CYP2C19 and VKORC1 in Iran. Pharmacol Rep. 2010. 62(4). Р.740–746. doi: 10.1016/s1734-1140(10)70332-7.
4. Borgiani P., Ciccacci C., Forte V., Romano S., Federici G., Novelli G. Allelic variants in the CYP2C9 and VKORC1 loci and interindividual variability in the anticoagulant dose effect of warfarin in Italians. Pharmacogenomics. 2007. 8(11). Р.1545-1550. doi: 10.2217/14622416.8.11.1545.
5. Cavallari L.H., Perera M.A. The future of warfarin pharmacogenetics in under-represented minority groups. Future Cardiol. 2012. 8(4). Р.563–576. doi: 10.2217/fca.
6. Céspedes-Garro C., Fricke-Galindo I., Naranjo M., Rodrigues-Soares F., Fariñas H., de Andrés F., López-López M., Peñas-Lledó E., LLerena A. Worldwide interethnic variability and geographical distribution of CYP2C9 genotypes and phenotypes. Expert Opin Drug Metab Toxicol. 2015. 11(12). Р.1893-1905. doi: 10.1517/17425255.2015.1111871.
7. Choi J.R.., Kim J.O., Kang D.R., Yoon S.A., Shin J.Y., Zhang X., Roh M.O., Hong H.J., Wang Y.P., Jo K.H., Lee K.S., Yun H.J., Oh Y.S., Yoo K.D., Jeon H.G., Lee Y.S., Kang T.S., Park H.J., Chung M.W., Kang J.H. Proposal of pharmacogenetics-based warfarin dosing algorithm in Korean patients. J Hum Genet. 2011. 56(4). Р.290-295. doi: 10.1038/jhg.2011.4.
8. Daly A.K., Rettie A.E., Fowler D.M., Miners J.O. Pharmacogenomics of CYP2C9: Functional and Clinical Considerations // Journal of Personalized Medicine. 2018. 8(1):1. URL: https://doi.org/10.3390/jpm8010001
9. Dean L. Warfarin Therapy and VKORC1 and CYP Genotype. Medical Genetics Summaries / National Library of Medicine. 2018. https://www.ncbi.nlm.nih.gov/books/NBK84174/
10. Fricke-Galindo I., Céspedes-Garro C., Rodrigues-Soares F., Naranjo M., Delgado Á., de Andrés F., López-López M., Peñas-Lledó E., LLerena A. Interethnic variation of CYP2C19 alleles, 'predicted' phenotypes and 'measured' metabolic phenotypes across world populations. Pharmacogenomics J. 2016. 16(2). P.113-123. doi: 10.1038/tpj.2015.70.
11. Holbrook A., Schulman S., Witt D.M., Vandvik P.O., Fish J., Kovacs M.J., Svensson P.J., Veenstra D.L., Crowther M., Guyatt G.H. 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. 2012. 141(2 Suppl). e152S-e184S. doi: 10.1378/chest.11-2295.
12. Iskakova A., Romanova A., Aitkulova A.., Sikhayeva N., Zholdybayeva E., Ramanculov E. Polymorphisms in genes involved in the absorption, distribution, metabolism, and excretion of drugs in the Kazakhs of Kazakhstan. BMC Genetics. 2016. 19;17:23. DOI 10.1186/s12863-016-0329-x
13. Kamal El-Din M.A., Farhan M.S., El Shiha R.I., El- Kaffas R.M., Mousa S.M. Frequency of CYP2C9 and VKORC1 gene polymorphisms and their influence on warfarin dose in Egyptian pediatric patients. Paediatr Drugs. 2014. 16(4). P.337–341.
14. King C.R., Deych E., Milligan P., Eby C., Lenzini P., Grice G., Porche-Sorbet R.M., Ridker P.M., Gage B.F. Gamma-glutamyl carboxylase and its influence on warfarin dose. Thromb Haemost. 2010.104(4). P.750-754. doi: 10.1160/TH09-11-0763.
15. Khalighi K., Cheng G., Mirabbasi S., Khalighi B., Wu Y., Fan W. Linkage disequilibrium between the CYP2C19*2,*17 and CYP2C9*1 alleles and impact of VKORC1, CYP2C9, CYP2C19 gene polymorphisms and gene-gene interactions on warfarin therapy. J Thromb Thrombolysis. 2017. 43(1). P.124-129. doi: 10.1007/s11239-016-1436-2.
16. Kumar K.D., Shewade D.G., Loriot M.A., Beaune P., Balachander J., Sai Chandran B.V., Adithan C. Effect of CYP2C9, VKORC1, CYP4F2 and GGCX genetic variants on warfarin maintenance dose and explicating a new pharmacogenetic algorithm in South Indian population. Eur J Clin Pharmacol. 2014. 70(1). P.47-56. doi: 10.1007/s00228-013-1581-x.
17. Lam M.P., Cheung B.M. The pharmacogenetics of the response to warfarin in Chinese // Br J Clin Pharmacol. 2012. 73(3). P.340-347. doi: 10.1111/j.1365-2125.2011.04097.x.
18. Li S., Zou Y., Wang X., Huang X., Sun Y., Wang Y., Dong L. and Jiang H. Warfarin dosage response related pharmacogenetics in Chinese population. PLoS One. 2015. 10(1): e0116463. doi: 10.1371/journal.pone.0116463.
19. Liu T.Y., Hsu H.Y., You Y.S., Hsieh Y.W., Lin T.C., Peng C.W., Huang H.Y., Chang S.S., Tsai F.J. Efficacy of Warfarin Therapy Guided by Pharmacogenetics: A Real-world Investigation Among Han Taiwanese. Clin Ther. 2023. 45(7). P.662-670. doi: 10.1016/j.clinthera.2023.04.006.
20. Lubitz S.A. Scott S.A., Rothlauf E.B., Agarwal A., Peter I., Doheny D., Van Der Zee S., Jaremko M., Yoo C., Desnick R.J., Halperin J.L. Comparative performance of gene-based warfarin dosing algorithms in a multiethnic population. J Thromb Haemost. 2010. 8(5). P.1018-1026. doi: 10.1111/j.1538-7836.2010.03792.x.
21. Purcell S., Neale B., Todd-Brown K., Thomas L., Ferreira MA., Bender D., Maller J., Sklar P., de Bakker PI., Daly MJ., Sham PC. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007. 81(3). P.559-575. doi: 10.1086/519795.
22. Rathore SS., Agarwal SK., Pande S., Singh SK., Mittal T., Mittal B. CYP4F2 1347 G> A & GGCX 12970 C> G polymorphisms: frequency in north Indians & their effect on dosing of acenocoumarol oral anticoagulant. The Indian Journal of Medical Research 2014. 139(4). P. 572-578.
23. Razavi FE., Zarban A., Hajipoor F., Naseri M. The allele frequency of CYP2C9 and VKORC1 in the Southern Khorasan population. Res Pharm Sci. 2017 12(3). P.211-221. doi: 10.4103/1735-5362.207202.
24. Rieder MJ., Reiner AP., Rettie AE. Gamma-glutamyl carboxylase (GGCX) tagSNPs have limited utility for predicting warfarin maintenance dose. J Thromb Haemost. 2007 5(11). P.2227-2234. doi: 10.1111/j.1538-7836.2007.02744.x.
25. Ross K.A., Bigham A.W., Edwards M., Gozdzik A., Suarez-Kurtz G., Parra E.J. Worldwide allele frequency distribution of four polymorphisms associated with warfarin dose requirements. Journal of human genetics. 2010. 55(9). P.582–589. doi: 10.1038/jhg.2010.73.
26. Sconce E.A., Khan T.I., Wynne H.A., Avery P., Monkhouse L., King B.P. 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). P.2329–2333. doi: 10.1182/blood-2005-03-1108.
27. Shayah K., Ghrewati A., Mohammad YA., Hadid I. Role of Genetic Variations in the CYP2C9 Gene in Determining the Optimal Dose of Warfarin in a Group of Syrian Patients. International Journal of Pharmaceutical Sciences and Nanotechnology. 2019. 12(2). P.4505-4511. doi.org/10.37285/ijpsn.2019.12.2.8
28. Sun Y., Wu Z., Li S., Qin X., Li T., Xie L., Deng Y., Chen J. Impact of gamma-glutamyl carboxylase gene polymorphisms on warfarin dose requirement: a systematic review and meta-analysis. Thromb Res. 2015. 135(4). P.739-747. doi: 10.1016/j.thromres.2015.01.029.
29. Wang D., Yong L., Zhang Q., Chen H. Impact of CYP2C19 gene polymorphisms on warfarin dose requirement: a systematic review and meta-analysis. Pharmacogenomics. 2022. 23(16). P.903-911. doi: 10.2217/pgs-2022-0106.
30. World Health Organization (WHO). Cardiovascular diseases. 2021. https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)
31. Yang L., Ge W., Yu F. and Zhu H. Impact of VKORC1 gene polymorphism on interindividual and interethnic warfarin dosage requirement-a systematic review and meta analysis. Thromb Res. 2010. 25(4). e159–e166. doi: 10.1016/j.thromres.2009.10.017.
32. Zhang J., Chen Z., Chen C. Impact of CYP2C9, VKORC1 and CYP4F2 genetic polymorphisms on maintenance warfarin dosage in Han-Chinese patients: A systematic review and meta-analysis. Meta Gene. 2016. P.197-209. doi: 10.1016/j.mgene.2016.07.002.
33. Zholdybayeva E., Iskakova A., Romanova A., Ramanculov E., Momynaliev K. Pharmacogenetic research in Kazakhstan. Cent Asian J Glob Health. 2014. 2(Suppl) P.87. doi: 10.5195/cajgh.2013.87.
34. Zhou Y., Lauschke VM. Population pharmacogenomics: an update on ethnogeographic differences and opportunities for precision public health. Hum Genet. 2022. 141(6). P.1113–1136. doi: 10.1007/s00439-021-02385-x.
35. Zhou Y., Nevosadová L., Eliasson E., Lauschke VM. Global distribution of functionally important CYP2C9 alleles and their inferred metabolic consequences. Hum Genomics. 2023. 17(1).15. doi: 10.1186/s40246-023-00461-z.
Количество просмотров: 56
Категория статей:
Оригинальное исследование
Библиографическая ссылка
Murtazaliyeva A.V., Berezinа G.M., Svyatova G.S., Yesset M.S., Burabayeva A.T. Prevalence of polymorphisms in warfarin metabolism-related genes among the Kazakh population // Nauka i Zdravookhranenie [Science & Healthcare]. 2025. Vol.27 (3), pp. 16-26. doi 10.34689/SH.2025.27.3.002Похожие публикации:
EPIDEMIOLOGY, RESOURCE DISTRIBUTION, AND MANAGEMENT CHALLENGES OF CHRONIC HEART FAILURE IN KAZAKHSTAN: A NATIONAL RETROSPECTIVE ANALYSIS
PREVALENCE OF POLYMORPHISMS IN WARFARIN METABOLISM-RELATED GENES AMONG THE KAZAKH POPULATION
NEUROLOGICAL COMPLICATIONS IN EXTRACORPOREAL MEMBRANE OXYGENATION: RISK FACTORS FOR THE DEVELOPMENT OF ACUTE CEREBROVASCULAR EVENTS
THE EFFECT OF REPAGLINIDE AND METFORMIN ON EXTERNAL RESPIRATORY FUNCTION IN PATIENTS WITH DIABETES AND ISCHEMIC HEART DISEASE ASSOCIATED WITH OBESITY
RETROSPECTIVE ANALYSIS OF PATIENTS WITH OBLITERATING ATHEROSCLEROSIS OF THE LOWER EXTREMITY ARTERIES IN THE ABAI REGION OF THE REPUBLIC OF KAZAKHSTAN