Association of genes CSK, MTHFR, АСЕ, ADRA2B, TCF7L2 with metabolic syndrome in indigenous and non-indigenous young residents of Western Siberia

Introduction. Due to the negative trend of growth of cardiovascular and endocrine diseases among young people, the need to study the genes involved in the development of metabolic disorders is becoming urgent.

Aim. To study the prevalence of variants of genes CSK, MTHFR, ACE, ADRA2B, TCF7L2 and their association with metabolic syndrome in indigenous and non-indigenous men and women living in the Khanty-Mansiysk autonomous okrug – Yugra. Materials and methods. The study involved 863 people living in the city of Surgut and in the Surgut district of the KhantyMansiysk autonomous okrug – Yugra aged 18 to 44 years. The indigenous population (280 people) is represented by 76 men and 204 women, the non–indigenous population (583 people) is represented by 207 men and 376 women. The DNA of genes CSK, ACE, ADRA2B, MTHFR and TCF7L2 was isolated by polymerase chain reaction.

Results. It was found that among indigenous (khanty) and non-indigenous men and women there are some differences in the prevalence of alleles and genotypes of gene variants in comparison with the international GnomAD database (v.3.1), which is associated with the peculiarities of ethnic composition and environment. The association of the rs1799752 variant of the gene ACE with metabolic syndrome was found in non-indigenous people: in women with the genotype ID (p = 0.027), in men with the genotype DD (p = 0.019).

Conclusion. Thus, there were no statistically significant differences between indigenous and non-indigenous residents in the frequency of alleles and genotypes of variants rs1378942 of the gene CSK, rs1801133 of the gene MTHFR, rs1799752 of the gene ACE, rs28365031 of the gene ADRA2B and rs7903146 of the gene TCF7L2. In the group of non-indigenous residents, the presence of metabolic syndrome is more often associated with the carrier variant rs1799752 of the gene ACE. The research results can be used to develop individual approaches to treatment and prevention that take into account the genetic characteristics of each person.

1. Michalsen VL, Wild SH, Kvaløy K, Svartberg J, Melhus M, Broderstad AR. Obesity measures, metabolic health and their association with 15-year allcause and cardiovascular mortality in the SAMINOR 1 Survey: a populationbased cohort study. BMC Cardiovasc Disord. 2021;21(1):510. https://doi.org/10.1186/s12872-021-02288-9.

2. Collins RL, Brand H, Karczewski KJ, Zhao X, Alföldi J, Francioli LC et al. A structural variation reference for medical and population genetics. Nature. 2020;581(7809):444–451. https://doi.org/10.1038/s41586-020-2287-8.

3. Mulerova T, Uchasova E, Ogarkov M, Barbarash O. Genetic forms and pathophysiology of essential arterial hypertension in minor indigenous peoples of Russia. BMC Cardiovasc Disord. 2020;20(1):169. https://doi.org/10.1186/s12872-020-01464-7.

4. Qian X, Li Y, Liu X, Tu R, Tian Z, Zhang H et al. C-src tyrosine kinase gene rs1378942 polymorphism and hypertension in Asians: Review and meta-analysis. Clin Chim Acta. 2018;487:202–209. https://doi.org/10.1016/j.cca.2018.10.003.

5. Lee HJ, Kang JO, Kim SM, Ji SM, Park SY, Kim ME et al. Gene Silencing and Haploinsufficiency of Csk Increase Blood Pressure. PLoS ONE. 2016;11(1):0146841. https://doi.org/10.1371/journal.pone.0146841.

6. Zhai Y, Yang J, Zhang J, Yang J, Li Q, Zheng T. Src-family Protein Tyrosine Kinases: A promising target for treating Cardiovascular Diseases. Int J Med Sci. 2021;18(5):1216–1224. https://doi.org/10.7150/ijms.49241.

7. Platunova IM, Nikulina SYu, Chernova AA, Prokopenko SV, Nikulin DA. The role of the CSK gene in the development of ischemic stroke. Modern Problems of Science and Education. 2016;(6). (In Russ.) Available at: https://science-education.ru/ru/article/view?id=25913.

8. Shestakova MV. The role of the tissue renin-angiotensin-aldosterone system in the development of metabolic syndrome, diabetes mellitus and itsvascular complications. Diabetes Mellitus. 2010;13(3):14–19. (In Russ.) https://doi.org/10.14341/2072-0351-5481.

9. Tiret L, Rigat B, Visvikis S, Breda C, Corvol P, Cambien F, Soubrier F. Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. Am J Hum Genet. 1992;51(1):197–205. Available at: https://pubmed.ncbi.nlm.nih.gov/1319114.

10. Liu JY, Yi YZ, Guo QW, Jia KX, Li XC, Cai JJ et al. Associations of ACE I/D and AGTR1 rs5182 polymorphisms with diabetes and their effects on lipids in an elderly Chinese population. Lipids Health Dis. 2024;23(1):231. https://doi.org/10.1186/s12944-024-02222-w.

11. Whaley-Connell A, Johnson MS, Sowers JR. Aldosterone: role in the cardiometabolic syndrome and resistant hypertension. Prog Cardiovasc Dis. 2010;52(5):401–409. https://doi.org/10.1016/j.pcad.2009.12.004.

12. Eldeeb HM, Elgharabawy RM, Abd Elmoniem AE, Ahmed AA. Alpha-2 beta-adrenergic receptor (301-303 I/D) gene polymorphism in hypertension and type 2 diabetes mellitus diseases among Saudi cases in the Qassim region. Sci Prog. 2021;104(2):368504211012162. https://doi.org/10.1177/00368504211012162.

13. Chen L, Wu C, Dong Z, Cao S, Ren N, Yan X. Methylenetetrahydrofolate reductase polymorphisms and elevated plasma homocysteine levels in small vessel disease. Brain Behav. 2023;13(5):2960. https://doi.org/10.1002/brb3.2960.

14. Liang Z, Li K, Chen H, Jia J, Li J, Huo Y. The Association of Plasma Homocysteine Concentrations with a 10-Year Risk of All-Cause and Cardiovascular Mortality in a Community-Based Chinese Population. Nutrients. 2024;16(12):1945. https://doi.org/10.3390/nu16121945.

15. Li R, Ou J, Li L, Yang Y, Zhao J, Wu R. The Wnt Signaling Pathway Effector TCF7L2 Mediates Olanzapine-Induced Weight Gain and Insulin Resistance. Front Pharmacol. 2018;9:379. https://doi.org/10.3389/fphar.2018.00379.

16. Cropano C, Santoro N, Groop L, Dalla Man C, Cobelli C, Galderisi A et al. The rs7903146 Variant in the TCF7L2 Gene Increases the Risk of Prediabetes/ Type 2 Diabetes in Obese Adolescents by Impairing β-Cell Function and Hepatic Insulin Sensitivity. Diabetes Care. 2017;40(8):1082–1089. https://doi.org/10.2337/dc17-0290.

17. Caro-Gomez MA, Naranjo-González CA, Gallego-Lopera N, Parra-Marín MV, Valencia DM, Arcos EG et al. Association of Native American ancestry and common variants in ACE, ADIPOR2, MTNR1B, GCK, TCF7L2 and FTO genes with glycemic traits in Colombian population. Gene. 2018;677:198–210. https://doi.org/10.1016/j.gene.2018.07.066.

18. Voevoda MI, Korneeva EV. Metabolic syndrome in young subjects residing in the Khanty-Mansi autonomous okrug – Yugra. Siberian Medical Review. 2023;(6):61–68. (In Russ.) Available at: https://smr.krasgmu.ru/journal/2369_8_voevoda.pdf.

19. Бутрова СА, Звенигородская ЛА, Кошельская ОА, Кухарчук ВВ, Мамедов МН, Медведева ИВ и др. Рекомендации экспертов всероссийского научного общества кардиологов по диагностике и лечению метаболического синдрома (второй пересмотр). 2009. Режим доступа: https://profmedforum.ru/assets/files/09-04-2018/metab1-vse.pdf.

20. Visseren FLJ, Mach F, Smulders YM, Carballo D, Koskinas KC, Bäck M et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021;42(34):3227–3237. https://doi.org/10.1093/eurheartj/ehab484.

21. Unger T, Borghi C, Charchar F, Khan NA, Poulter NR, Prabhakaran D et al. 2020 International Society of Hypertension Global Hypertension Practice Guidelines. Hypertension. 2020;75(6):1334–1357. https://doi.org/10.1161/HYPERTENSIONAHA.120.15026.

22. Födinger M, Hörl WH, Sunder-Plassmann G. Molecular biology of 5,10-methylenetetrahydrofolate reductase. J Nephrol. 2000;13(1):20–33. Available at: https://pubmed.ncbi.nlm.nih.gov/10720211/.

23. Lindpaintner K, Pfeffer MA, Kreutz R, Stampfer MJ, Grodstein F, LaMotte F et al. A prospective evaluation of an angiotensin-converting-enzyme gene polymorphism and the risk of ischemic heart disease. N Engl J Med. 1995;332(11):706–711. https://doi.org/10.1056/NEJM199503163321103.

24. Fujimura H, Kawasaki T, Sakata T, Ariyoshi H, Kato H, Monden M, Miyata T. Common C677T polymorphism in the methylenetetrahydrofolate reductase gene increases the risk for deep vein thrombosis in patients with predisposition of thrombophilia. Thromb Res. 2000;98(1):1–8. https://doi.org/10.1016/s0049-3848(99)00231-5.

25. Snapir A, Heinonen P, Tuomainen TP, Alhopuro P, Karvonen MK, Lakka TA et al. An insertion/deletion polymorphism in the alpha2B-adrenergic receptor gene is a novel genetic risk factor for acute coronary events. J Am Coll Cardiol. 2001;37(6):1516–1522. https://doi.org/10.1016/s0735-1097(01)01201-3.

26. Phan L, Jin Y, Zhang H, Qiang W, Shekhtman E, Shao D et al. ALFA: Allele Frequency Aggregator. National Center for Biotechnology Information, U.S. National Library of Medicine. 2020. Available at: www.ncbi.nlm.nih.gov/snp/docs/gsr/alfa/.

27. Trifonova EA, Eremina ER, Urnov FD, Stepanov VA. Genetic diversity and structure of linkage disequilibrium of the MTHFR gene in populations of Northern Eurasia. Acta Naturae. 2012;4(1):53–69. Available at: https://cyberleninka.ru/article/n/geneticheskoe-raznoobrazie-i-strukturaneravnovesiya-po-stsepleniyu-gena-mthfr-v-populyatsiyah-severnoyevrazii.

28. Gubina MA, Babenko VN, Batsevich VA, Leibova NA, Zabiyako AP. Polymorphism of mitochondrial DNA and six nuclear genes in the Amur Evenk population. Genetics. 2022;58(1):52–67. (In Russ.) https://doi.org/10.31857/S0016675822010039.

29. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434–443. https://doi.org/10.1038/s41586-020-2308-7.

30. Kubanova AP, Zotova TYu, Azova MM, Aissa A Ait. The ACE gene polymorphism influence on the course of hypertension in the Caucasians as part of the metabolic syndrome. Journal of New Medical Technologies. 2016;23(4):66–70. (In Russ.) Available at: https://cyberleninka.ru/article/n/vliyanie-polimorfizma-gena-ace-na-techenie-arterialnoy-gipertenzii-vramkah-metabolicheskogo-sindroma.

31. Mulerova TA, Tsygankova DP, Ogarkov MYu. Polymorphic variants of ACE, AGT, AGTR1, MTHFR and NOS3 candidate genes connected with arterial hypertension as part of the metabolic syndrome among the shor people. Obesity and Metabolism. 2021;18(2):190–197. (In Russ.) https://doi.org/10.14341/omet12295.

32. Kumari N, Ahirwar R, Yadav A, Ramakrishnan L, Sagar SK. Mondal PR. ACE Gene I/D Polymorphism and Cardiometabolic Risk Factors: A Cross Sectional Study of Rural Population. Biochem Genet. 2024;62(2):1008–1020. https://doi.org/10.1007/s10528-023-10462-1.