Prevalence of AOX1 and CYP1A2 gene polymorphisms associated with response to favipiravir therapy in novel coronavirus infection COVID-19 among ethnic groups of the North Caucasus

Drug sensitivity to, in particular to favipiravir, may vary among representatives of different ethnic groups. Studies have previously shown that carrying certain variants of the AOX1 and CYP1A2 genes may be associated with an increased incidence of adverse reactions with patients having COVID-19 and taking favipiravir. This work is devoted to studying the prevalence of mutant variants rs55754655 and rs10931910 of the AOX1 gene and rs762551 of the CYP1A2 gene in various ethnic groups of the North Caucasus.

The aim. To characterize the distribution structure of AOX1 (rs55754655 and rs10931910) and CYP1A2 (rs762551) variants among the peoples of the North Caucasus (Ossetians, Balkars, Kabardians, Avars, Dargins, Laks, Kumyks and Lezgins).

Materials and methods. The frequency of distribution of AOX1 and CYP1A2 gene variants was studied among 897 conditionally healthy volunteers (362 men — 40.4% and 535 women — 59.6%; average age — 34.6±6.3%), from 8 ethnic groups of the North Caucasus: Ossetians, Balkars, Kabardians, Avars, Dargins, Laks, Kumyks and Lezgins (n=100 for each), as well as 97 Russians (reference group).

Results. As a result of the analysis, a significant difference was found in the allele frequencies for the rs10931910 AOX1 genetic polymorphism between Balkars and Russians (p <0.05), Laks and Russians (p <0.05), and especially between Dargins and Russians (p <0.0001). No statistically significant differences in the allele frequencies of the CYP1A2 gene were found in the comparative analysis of ethnic groups with the comparison group.

Conclusion. Significant differences were revealed in the frequency of AOX1 polymorphisms (rs10931910, rs55754655) in the peoples of the North Caucasus relative to the Russian population. The largest deviations were recorded in Dargins: a decrease in the frequency of the minor allele rs10931910 to 28.5% (p <0.0001) and rs55754655 to 3.0% (p=0.0105). The results may be useful for optimizing therapy with medicines that are AOX1 substrates, which include favipiravir, used to treat patients with COVID-19.

1. Ghasemnejad-Berenji M, Pashapour S. Favipiravir and COVID-19: A Simplified Summary. Drug Res (Stuttg). 2021;71(3):166–170. DOI: 10.1055/a-1296-7935

2. Korula P, Alexander H, John JS, Kirubakaran R, Singh B, Tharyan P, Rupali P. Favipiravir for treating COVID-19. Cochrane Database Syst Rev. 2024;2(2):CD015219. DOI: 10.1002/14651858.CD015219.pub2

3. Madelain V, Nguyen TH, Olivo A, de Lamballerie X, Guedj J, Taburet AM, Mentré F. Ebola Virus Infection: Review of the Pharmacokinetic and Pharmacodynamic Properties of Drugs Considered for Testing in Human Efficacy Trials. Clin Pharmacokinet. 2016;55(8):907–923. DOI: 10.1007/s40262-015-0364-1

4. Filimonov DA, Lagunin AA, Gloriozova TA, Rudik AV, Druzhilovskii DS, Pogodin PV. Prediction of the biological activity spectra of organic compounds using the pass online web resource. Chem Heterocycl Compd. 2014;50(3):444–457. DOI: 10.1007/S10593-014-1496-1/METRICS

5. Temirbulatov II, Kryukov AV, Mirzaev KB, Denisenko NP, Abdullaev SP, Petrova AV, Tkach EP, Shipacheva AV, Sychev DA. Pharmacogenetic Markers of Favipiravir Safety in COVID-19 Treatment. Antibiotics and Chemotherapy. 2023;68(5–6):55–61. DOI: 10.37489/0235-2990-2023-68-5-6-55-61-61

6. Kurzawski M, Dziewanowski K, Safranow K, Drozdzik M. Polymorphism of genes involved in purine metabolism (XDH, AOX1, MOCOS) in kidney transplant recipients receiving azathioprine. Ther Drug Monit. 2012;34(3):266–274. DOI: 10.1097/FTD.0b013e31824aa681

7. Bozkurt I, Gözler T, Yüksel I, Ulucan K, Tarhan KN. Prognostic Value of CYP1A2 (rs2069514 and rs762551) Polymorphisms in COVID-19 Patients. Balkan J Med Genet. 2023;26(1):35–42. DOI: 10.2478/bjmg-2023-0005

8. Romodanovsky DP, Khapaev BA, Ignatiev IV, Kukes VG, Karkishchenko VN. Frequencies of "slow" allelic variants of genes encoding cytochrome P450 isoenzymes CYP2D6, CYP2C19, CYP2C9 in Karachays and Circassians. Biomedicine. 2010;1(2):33–37. EDN: NTVJLV. Russian

9. Baturin VA, Tsarukyan AA, Kolodijchuk EV. Study of CYP2C9 gene polymorphism in ethnic groups of the population of Stavropol region. Medical News of North Caucasus. 2014;9(1):45–48. DOI: 10.14300/mnnc.2014.09013

10. Mirzaev KB, Fedorinov DS, Ivashchenko DV, Sychev DA. ADME pharmacogenetics: future outlook for Russia. Pharmacogenomics. 2019;20(11):847–865. DOI: 10.2217/pgs-2019-0013

11. Abdullaev SP, Denisenko NP, Mirzaev KB, Shuev GN, Sozaeva ZA, Kachanova AA, Mammaev SN, Kasaeva EA, Gafurov DM, Grishina EA, Sychev DA. CYP2C8, PTGS-1, 2 gene polymorphisms prevalence associated with sensitivity to non-steroidal anti-inflammatory drugs among North Caucasus ethnic groups. Terapevticheskii arkhiv. 2021;93(11):1334–1339. DOI: 10.26442/00403660.2021.11.201220

12. Demir E, Sütcüoğlu O, Demir B, Ünsal O, Yazıcı O. A possible interaction between favipiravir and methotrexate: Drug-induced hepatotoxicity in a patient with osteosarcoma. J Oncol Pharm Pract. 2022;28(2):445–448. DOI: 10.1177/10781552211031304

13. Tang H, Quertermous T, Rodriguez B, Kardia SL, Zhu X, Brown A, Pankow JS, Province MA, Hunt SC, Boerwinkle E, Schork NJ, Risch NJ. Genetic structure, self-identified race/ethnicity, and confounding in case-control association studies. Am J Hum Genet. 2005;76(2):268–275. DOI: 10.1086/427888

14. Yunusbayev B, Kutuev I, Khusainova R, Guseinov G, Khusnutdinova E. Genetic structure of Dagestan populations: a study of 11 Alu insertion polymorphisms. Hum Biol. 2006;78(4):465–476. DOI: 10.1353/hub.2006.0059

15. Balanovska EV, Abdulaev SP, Gorin IO, Belov RO, Mukatdarova EA, Pylev VY. Gene geography of pharmacogenetically significant CYP2C19 cytochrome superfamily DNA markers in the populations of Russia and neighboring countries. Bulletin of RSMU. 2023;(5):26–40. DOI: 10.24075/brsmu.2023.039

16. Harrison PW, Amode MR, Austine-Orimoloye O, et al. Ensembl 2024. Nucleic Acids Res. 2024;52(D1):D891–D899. DOI: 10.1093/nar/gkad1049

17. Balanovska EV, Petrushenko VS, Koshel SM, Pocheshkhova EA, Chernevskiy DK, Mirzaev KB, Abdullaev SP, Balanovsky OP. Cartographic atlas of frequency variation for 45 pharmacogenetic markers in populations of Russia and its neighbor states. Bulletin of RSMU. 2020;(6):38–50. DOI: 10.24075/brsmu.2020.080

18. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020;323(18):1824–1836. DOI: 10.1001/jama.2020.6019

19. Whirl-Carrillo M, Huddart R, Gong L, Sangkuhl K, Thorn CF, Whaley R, Klein TE. An Evidence-Based Framework for Evaluating Pharmacogenomics Knowledge for Personalized Medicine. Clin Pharmacol Ther. 2021;110(3):563–572. DOI: 10.1002/cpt.2350

20. Ueda H, Narumi K, Furugen A, Saito Y, Kobayashi M. Thers35217482 (T755I) single-nucleotide polymorphism in aldehyde oxidase-1 attenuatesproteindimer formation and reduces the rates of phthalazine metabolism. Drug Metab Dispos. 2022:DMD-AR-2022-000902. DOI: 10.1124/dmd.122.000902

21. Garattini E, Fratelli M, Terao M. Mammalian aldehyde oxidases: genetics, evolution and biochemistry. Cell Mol Life Sci. 2008; 65(7–8):1019–1048. DOI: 10.1007/s00018-007-7398-y

22. Obach RS, Huynh P, Allen MC, Beedham C. Human liver aldehyde oxidase: inhibition by 239 drugs. J Clin Pharmacol. 2004;44(1):7–19. DOI: 10.1177/0091270003260336

23. Kitamura S, Sugihara K, Ohta S. Drug-metabolizing ability of molybdenum hydroxylases. Drug Metab Pharmacokinet. 2006;21(2):83–98. DOI: 10.2133/dmpk.21.83

24. Konishi K, Fukami T, Gotoh S, Nakajima M. Identification of enzymes responsible for nitrazepam metabolism and toxicity in human. Biochem Pharmacol. 2017;140:150–160. DOI: 10.1016/j.bcp.2017.06.114

25. Amano T, Fukami T, Ogiso T, Hirose D, Jones JP, Taniguchi T, Nakajima M. Identification of enzymes responsible for dantrolene metabolism in the human liver: A clue to uncover the cause of liver injury. Biochem Pharmacol. 2018;151:69–78. DOI: 10.1016/j.bcp.2018.03.002

26. Morgan SL, Baggott JE. The importance of inhibition of a catabolic pathway of methotrexate metabolism in its efficacy for rheumatoid arthritis. Med Hypotheses. 2019;122:10–15. DOI: 10.1016/j.mehy.2018.10.002

27. Smith MA, Marinaki AM, Arenas M, Shobowale-Bakre M, Lewis CM, Ansari A, Duley J, Sanderson JD. Novel pharmacogenetic markers for treatment outcome in azathioprine-treated inflammatory bowel disease. Aliment Pharmacol Ther. 2009;30(4):375–384. DOI: 10.1111/j.1365-2036.2009.04057.x

28. Carroll MB, Smith DM, Shaak TL. Genomic sequencing of uric acid metabolizing and clearing genes in relationship to xanthine oxidase inhibitor dose. Rheumatol Int. 2017;37(3):445–453. DOI: 10.1007/s00296-016-3592-2

29. Ramírez J, Kim TW, Liu W, Myers JL, Mirkov S, Owzar K, Watson D, Mulkey F, Gamazon ER, Stock W, Undevia S, Innocenti F, Ratain MJ. A pharmacogenetic study of aldehyde oxidase I in patients treated with XK469. Pharmacogenet Genomics. 2014;24(2):129–132. DOI: 10.1097/FPC.0000000000000023