Biomics

Studying the territorial features of the genetic structure of open populations in industrial centers of Siberia is essential for developing biomedical monitoring databases. This study aimed to analyze the distribution of genotype, allele, and multi-locus combination frequencies of the CYP2R1, CYP27A1, CYP27B1, and CYP24A1 genes in the modern Russian population of the Kemerovo Oblast – Kuzbass (RUS-KEM group, n=254). Genotyping of eight polymorphic markers was performed using real-time PCR. Aggregated data from the ALFA project (2024 release) for European (EUR) and East Asian (EAS) superpopulations, alongside the Russian Federation Population Frequency Database of the FMBA (2025 release, RUS-RF group), were used as reference groups for comparison. Adherence to the Hardy–Weinberg equilibrium was observed for 7 out of 8 loci. For the catabolic variant CYP24A1(rs2209314), a statistically significant deviation from the Hardy–Weinberg equilibrium was revealed (p_HWE < 0.001), accompanied by a pronounced heterozygote deficiency (D = -0.227) and an accumulation of T/T homozygotes (62.99%), which is driven by sample subdivision (Wahlund effect) and the impact of environmental pressure. An accumulation of alternative variants was recorded for the 1-alpha-hydroxylase gene loci (CYP27B1(rs10877012, T frequency – 0.646; CYP27B1(rs4646536, G frequency – 0.514) compared to average Russian and European values. Analysis of M. Nei genetic distances (d) revealed the shifting of the RUS-KEM group away from the comparison groups, forming a specific vector of differentiation toward East Asian trends (d = 0.069). Multi-locus combination analysis using configurational frequencies revealed a non-random distribution of three- and four-locus complexes with a pronounced cumulative enrichment effect (O/E indexes up to 1.55). The TGG and TGA triplets dominated within the CYP27B1(rs10877012) – CYP27B1(rs4646536) – CYP24A1(rs2296241) locus system, showing a distinct fixing effect of the functionally active CYP27B1 rs4646536:G allele. The results form a fundamental basis for subsequent regional biomedical monitoring under the combined climate-technogenic pressure of the Siberian region.

population genetics, gene polymorphism, cytochromes P450, vitamin D hydroxylation system, Kuzbass, allele frequencies

1. Babushkina NP, Postrigan AE, Kucher AN et al. Associations of rs4244285 in the CYP2C19 gene with multifactorial diseases. The Siberian Journal of Clinical and Experimental Medicine. 2021. 36(4). 125–131. doi: 10.29001/2073-8552-2021-36-4-125-131. (In Russian)
2. Bahrami A, Mehramiz M, Ghayour-Mobarhan M et al. A genetic variant in the cytochrome P450 family 2 subfamily R member 1 determines response to vitamin D supplementation. Clinical Nutrition. 2019. 38(2). 676–681. doi: 10.1016/j.clnu.2018.11.007
3. Bakanova ML, Minina VI, Savchenko YA et al. The role of polymorphic variants of xenobiotic biotransformation enzyme genes in the pathogenesis of lung adenocarcinoma. Medical Genetics. 2020. 19(6), 79–80. doi: 10.25557/2073-7998.2020.06.79-80. (In Russian)
4. Balanovskaya EV, Petrushenko VS, Koshel’ SM et al. 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
5. Belyaeva E.V., Ershova O.A., Astakhova T.A., Bugun O.V. Polymorphism of glutathione‑S‑transferase genes in ethnic groups residing in Eastern Siberia. Vavilov Journal of Genetics and Breeding. 2017. 21(5). 576–580. doi: 10.18699/VJ17.274.
6. Burke CA, Baron JA. Genetic variants in CYP2R1, CYP24A1, and VDR modify the efficacy of vitamin D3 supplementation for increasing serum 25-hydroxyvitamin D levels in a randomized controlled trial. Journal of Clinical Endocrinology and Metabolism. 2014. 99(10). E2133-2137. doi: 10.1210/jc.2014-1389
7. Carlberg C. Vitamin D signaling network and the immune system: Focus on P450 cytochromes expression. Frontiers in Immunology. 2023. 14. 1124503. doi: 10.3389/fimmu.2023.1124503
8. Dimitrov V, White JH. Species-specific regulation of innate immunity by vitamin D signaling and hydroxylases genetic architecture. Journal of Steroid Biochemistry and Molecular Biology. 2022. 219. 106063. doi: 10.1016/j.jsbmb.2022.106063
9. Dzhaubermezov M.A., Mingazheva E.T., Axberg D.S., Ekomasova N.V., Khusnutdinova E.K. Polymorphism of the cytochrome P450 CYP1A1 (Ile462Val) gene in the populations of Balkars and Karachays. Ecological Genetics. 2021;19(3):273-279. doi: 10.17816/ecogen71456 (In Russian)
10. Dzhaubermezov M, Ekomasova N, Mustafin RN et al. Genetic Polymorphisms of Cytochromes P450 in Finno-Permic Populations of Russia. Genes. 2022. 13(12). 2353. doi: 10.3390/genes13122353
11. Gromova OA, Torshin IYu, Chuchalin AG. Molecular synergists of vitamin D: The role of cytochrome P450 and regulation of the inflammatory response via the NF‑κB signaling pathway. Terapevticheskii Arkhiv. 2023. 95(4). 312–320. doi: 10.26442/00403660.2023.04.202145. (In Russian)
12. Hribar M., Hristov H., Gregorič M., Blaznik U., Zaletel K., Oblak A., Osredkar J., Kušar A., Žmitek K., Rogelj I. Nutrihealth Study: Seasonal Variation in Vitamin D Status Among the Slovenian Adult and Elderly Population. Nutrients. 2020. 12(6). 1838. doi: 10.3390/nu12061838.
13. Karrow NA, Leuschner SE, Shandilya UK et al. Genetic Variants Influencing Individual Vitamin D Status. Nutrients. 2024. 16(4). 1112. doi: 10.3390/nu16041112
14. Kochetova OV, Korytina GF, Akhmadishina LZ et al.Analysis of the cytochrome P450 1A1 (CYP1A1) gene polymorphism in the ethnic groups of the republic of Bashkortostan. Russ J Genet. 2008. 44. 1454–1460. doi:10.1134/S1022795408120107
15. Korytina GF, Akhmadishina LZ, Victorova TV. Frequencies of CYP1B1 and CYP2F1 polymorphic variants in three ethnic groups of Bashkortostan and in patients with chronic obstructive pulmonary disease. Molecular Biology. 2010. 44(1). 33–41. doi: 10.1134/S002689331001005X
16. Marusin AV, Stepanov VA, Spiridonova MG. Polymorphism of genes of ethanol-metabolizing enzymes ADH1B, ADH7, and CYP2E1 in the Russian population of the West Siberian region. Medical Genetics. 5(7). 51–56. (In Russian)
17. Ostaptseva AV, Shabaldin AV, Zorkoltseva IV. Genetic polymorphism of the CYP1A2 gene in Teleuts and Shors of the Kemerovo Region. Medicine in Kuzbass. 5(1). 10–12. (In Russian)
18. Popova SN, Spiridonova MG, Stepanov VA. Analysis of variability in genes involved in nutrient and vitamin metabolism in Siberian populations in the context of ecological adaptation. Vavilovskii Zhurnal Genetiki i Selektsii. 2024. 28(2). 184–192. doi:18699/VJ24.021
19. Raczyk M., Carlberg C. From Sunlight to Signaling: Evolutionary Integration of Vitamin D and Sterol Metabolism. 2024. 14(1). 42. doi: 10.3390/metabo14010042
20. Rahimkulova A.A., Akhmetova V.L., Malievsky O.A., Khusnutdinova E.K. Congenital Adrenal Hyperplasia: Clinical and Genetic Aspects. Medical Genetics. 2013. 12(6). 3–14.
21. Revez J, Lin T, Qiao Z et al. Genome-wide association study highlights CYP24A1 mechanisms and vitamin D concentrations. Nature Communications. 11(1). 1432. doi: 10.1038/s41467-020-15112-3
22. Sanchez-Podme E, Flores-Alvarado D. Polymorphisms CYP2R1 rs10766197 and CYP27B1 rs10877012 in Multiple Sclerosis: A Case-Control Study. Multiple Sclerosis and Related Disorders. 2021. 56. 103254. doi: 10.1016/j.msard.2021.103254
23. Viktorova TV, Korytina GF, Makarova OV et al. Polymorphism of the Arylamine N-Acetyltransferase 2 Gene in Ethnic Populations of the Volga–Ural Region. Molecular Biology. 2003. 37(6). 827–829. doi:1023/B:MBIL.0000008349.44814.20
24. Zhou A, Hyppönen E. Long-term vitamin D status and inflammatory biomarkers: A Mendelian randomization study highlighting NF-kB signaling modification. International Journal of Epidemiology. 2023. 52(2). 523–534. doi: 10.1093/ije/dyac164