The nature of the association of IL10 gene single nucleotide polymorphisms (rs1800896 and rs1800872) with the development of primary open-angle glaucoma in patients from different regions of Russia based on the results of a multicenter study

One of the development factors of primary open-angle glaucoma (POAG) is genetic predisposition to its occurrence, associated with the peculiarity of cytokine genes. However, mechanisms for the implementation of this phenomenon for different geographic regions remain unknown. The aim of the study analyze the distribution features of the single nucleotide polymorphisms of IL10 gene (rs1800896 and rs1800872) in groups of patients with POAG from four regions of the Russian Federation: Novosibirsk (NSR), Leningrad (LEN), Orenburg (ORE) regions and the Chuvash Republic (CHVSh).

Material and methods. The comparative multicenter genetic study on 499 patients with POAG from 4 branches of the S. Fyodorov Eye Microsurgery Federal State Institution (Novosibirsk – 199 people, Cheboksary – 100 people, Orenburg – 100 people, St. Petersburg – 100 people) was conducted. The control group – 530 individuals without this disease. Genotyping was performed by TaqMan (Syntol, Russia). Differences were considered statistically significant at p < 0.05, with Bonferroni correction.

Results and discussion. Statistically significant multidirectional interregional differences in the distribution of IL10 gene polymorphisms in POAG patients were revealed. The frequency of IL10-592 C allele in patients from the LEN region have increased to 87.00 % relative to patients from NSO (72.86 %, odds ratio (OR) = 2.50, p_cor = 0.0006) and from ORE (75.50 %, OR = 2.17, p_cor = 0.0276), as well as IL10-592 CC genotype. LEN region patients with this genotype have 3.57-fold higher chance of POAG developing than NSO patients (p_cor = 0.0006) and 2.86-fold higher chance – relative to ORE residents (p_cor = 0.0084). In LEN region patients the frequencies of IL10-592 A, IL10-592 CA and IL10-592CA / IL10-1082AA complex genotype were reduced relative to patients from the ORE (24.00 %, OR = 6.00, p_cor = 0,0016). This complex is, on the one hand, protective against POAG disease for residents of the LEN region, and on the other hand, a risk factor for the development of POAG in residents of the NSR and the ORE.

Conclusions. We have identified new factors of genetic predisposition to the POAG development in Russian Federation and identified both positive and negative associative links with this ophthalmopathology. The results can be used to develop polygenic risk indicators for the POAG development, taking into account regional ethnogeographic specifics.

1. Yadav M., Bhardwaj A., Yadav A., Dada R., Tanwar M. Molecular genetics of primary open-angle glaucoma. Indian J. Ophthalmol. 2023;71(5):1739–1756. doi: 10.4103/IJO.IJO_2570_22

2. Goldmann O., Nwofor O.V., Chen Q., Medina E. Mechanisms underlying immunosuppression by regulatory cells. Front. Immunol. 2024;15:1328193. doi: 10.3389/fimmu.2024.1328193

3. Garlet G.P., Martins W. Jr., Fonseca B.A., Ferreira B.R., Silva J.S. Matrix metalloproteinases, their physiological inhibitors and osteoclast factors are differentially regulated by the cytokine profile in human periodontal disease. J. Clin. Periodontol. 2004;31(8):671– 679. doi: 10.1111/j.1600-051X.2004.00545.x

4. Moore K.W., de Waal Malefyt R., Coffman R.L., O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 2001;19:683–765. doi: 10.1146/annurev.immunol.19.1.683

5. Moudi B., Heidari Z., Mahmoudzadeh-Sagheb H., Hashemi M., Metanat M., Khosravi S., Farrokh P. Association between IL-10 gene promoter polymorphisms (-592 A/C, -819 T/C, -1082 A/G) and susceptibility to HBV infection in an Iranian population. Hepat. Mon. 2016;16(2):e32427. doi: 10.5812/hepatmon.32427

6. Zhang G., Manaca M.N., McNamara-Smith M., Mayor A., Nhabomba A., Berthoud T.K., Khoo S-K., Wiertsema S., Aguilar R., Barbosa A.,…Dobaño C. Interleukin-10 (IL-10) polymorphisms are associated with IL-10 production and clinical malaria in young children. Infect. Immun. 2012;80(7):2316–2322. doi: 10.1128/IAI.00261-12

7. Berglundh T., Donati M., Hahn-Zoric M., Hanson L.A., Padyukov L. Association of the -1087 IL 10 gene polymorphism with severe chronic periodontitis in swedish caucasians. J. Clin. Periodontol. 2003;30(3):249–254. doi: 10.1034/j.1600-051x.2003.10274.x

8. Sumer A.P., Kara N., Keles G.C., Gunes S., Koprulu H., Bagci H. Association of interleukin-10 gene polymorphisms with severe generalized chronic periodontitis. J. Periodontol. 2007;78(3):493–497. doi: 10.1902/jop.2007.060309

9. Fowler E.V., Eri R., Hume G., Johnstone S., Pandeya N., Lincoln D., Templeton D., Radford-Smith G.L. TNFalpha and IL10 SNPs act together to predict disease behaviour in Crohn’s disease. J. Med. Genet. 2005;42(6):523–528. doi: 10.1136/jmg.2004.027425

10. Stanilova S.A., Miteva L.D., Karakolev Z.T., Stefanov C.S. Interleukin-10-1082 promoter polymorphism in association with cytokine production and sepsis susceptibility. Intensive Care Med. 2006;32(2):260– 266. doi: 10.1007/s00134-005-0022-4

11. Crawley E., Kay R., Sillibourne J., Patel P., Hutchinson I., Woo P. Polymorphic haplotypes of the interleukin-10 5’ flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. Arthritis. Rheum. 1999;42(6):1101–1108. doi: 10.1002/1529-0131(199906)42:63.0.CO;2-Y

12. Liu F., Li B., Wang W.T., Wei Y.G., Yan L.N., Wen T.F., Xu M.Q., Yang J.Y. Interleukin-10-1082G/A polymorphism and acute liver graft rejection: A meta-analysis. World J. Gastroenterol. 2012;18(8):847– 854. doi: 10.3748/wjg.v18.i8.847

13. Wilson J.N., Rockett K., Keating B., Jallow M., Pinder M., Sisay-Joof F., Newport M., Kwiatkowski D. A hallmark of balancing selection is present at the promoter region of interleukin 10. Genes Immun. 2006;7(8):680–683. doi: 10.1038/sj.gene.6364336

14. Averin A.N., Ponedelkov A.V., Bandurin A.P. National and ethnic composition of the russian population. Gumanitarnye, social’no-ekonomicheskie i obshchestvennye nauki = Humanities, social-economic and social sciences. 2023;(8):15–19. [In Russian]. doi: 10.23672/SAE.2023.28.58.039

15. Abdullaev S.M., Tselishcheva Yu.I., Samokhodskaya L.M., Bochkov V.N., Kvasovka V.V., Ignatova T.M., Krasnova T.N., Mukhin N.A. Genetic markers of predisposition to an aggressive course of chronic C hepatitis. Vestnik Rossiyskoy akademii meditsinskikh nauk = Annals of the Russian Academy of Medical Sciences. 2007;(1):8–13. [In Russian].

16. Goncharova I.A., Bragina E.Yu., Zhalsanova I.Zh., Babushkina N.P., Gomboeva D.E. Effect of IL10 (rs1800872) and CXCL10 (rs4386624, rs4256246) genes polymorphism in the development of viral and bacterial infectious diseases. Nauchnye rezul’taty biomeditsinskikh issledovaniy = Research Results in Biomedicine. 2019;5(4):32–43. [In Russian]. doi: 10.18413/2658-6533-2019-5-4-0-3

17. Baranova N.I., Molotilov B.A., Ashchina L.A., Shkurova N.A. Role of IL-1β, TNF-α, IL-10, IL-17, and IL-4 gene polymorphisms in the pathogenesis of chronic rhinosinusitis with nasal polyps. Russkiy meditsinskiy zhurnal. Meditsinskoye obozrenie = Russian Medical Journal. Medical Review. 2022;6(2):57–61 [In Russian]. doi: 10.32364/2587-6821-2022-6-2-57-61

18. Svitina S.P., Sidorova Zh.Yu., Kostroma I.I., Zhernyakova A.A., Chechetkin A.V., Chubukina Zh.V., Gritsaev S.V., Kapustin S.I., Bessmel’tsev S.S. Polymorphism of interleukins and tumor necrosis factor α genes in multiple myeloma patients with autologous hematopoietic stem cell transplantation. Klinicheskaya onkogematologiya = Clinical Oncohematology. 2021;14(3):340–346. [In Russian]. doi: 10.21320/2500-2139-2021-14-3-340-346

19. Zhorina Yu.V., Abramovskikh O.S., Ignatova G.L., Ploshchanskaya O.G. Analysis of associations of polymorphisms in the genes coding for L4, IL10, IL13 with the development of atopic bronchial asthma and its remission. Vestnik Rossiyskogo gosudarstvennogo meditsinskogo universiteta = Bulletin of the Russian State Medical University. 2019;(5):87–91. [In Russian]. doi: 10.24075/vrgmu.2019.067

20. Liu L., Zheng F. IL-10 -1082A/G, -592C/A, and -819T/C polymorphisms in association with lung cancer susceptibility: a meta-analysis. Onco Targets Ther. 2016;9:6083–6091. doi: 10.2147/OTT.S118481

21. Wei X., Wang Y., Kang M., Jiang H., Liu C., Tang, W., Qiu H., Zhang Sh., Jiang J. Polymorphisms in the interleukin-10 gene and Graves’ disease: a meta-analysis. Int. J. Clin. Exp. Med. 2017;10(2):1847– 1856. Available at: clck.ru/3N7Pd3

22. Shevchenko A.V., Prokof’ev V.F., Konenkov V.I., Chernykh V.V., Ermakova O.V., Trunov A.N. Analysis of IL1B (rs1143627), IL4 (rs2243250), IL6 (rs1800795), IL8 (rs4073), IL10 (rs1800896, rs1800872), IL17A (rs227593) cytokines genes polymorphism and its complex genotypes among Caucasian patients of Western Siberia with primary open-angle glaucoma. Immunologiya = Immunology. 2021;42(3):211–221. [In Russian]. doi: 10.33029/0206-4952-2021-42-3211-221

23. Konenkov V.I., Prokofiev V.F., Shevchenko A.V., Golovanova O.V. The cytokine gene polymorphism as a factor of the demographic structure of the Caucasoid population in Siberia. Immunologiya = Immunology. 2011;32(2):60–65. [In Russian].

24. Konenkov V.I., Shevchenko A.V., Prokofiev V.F., Trunov A.N., Chernykh V.V. Constitutional risk factors for the development of glaucoma and cataracts in the Europioid population of Russia. Byulleten’ sibirskoy meditsiny = Bulletin of Siberian Medicine. 2023;22(3):43–53. [In Russian]. doi: 10.20538/1682-0363-2023-3-43-53

25. Zhang Y.H., Xing Y.Q., Chen Z., Ma X.C., Lu Q. Association between interleukin-10 genetic polymorphisms and risk of primary open angle glaucoma in a Chinese Han population: a case-control study. Int. J. Ophthalmol. 2019;12(10):1605–1611. doi: 10.18240/ijo.2019.10.13

26. Boyko I.I., Dolgova A.P., Kharitonova V.G. The population of Chuvashia about the republic: general assessment and ethnic peculiarities (results of three waves of the study). Vestnik Chuvashskogo universiteta = Bulletin of the Chuvash University. 2018;(4):13–20. [In Russian].