Association of polymorphic variants of cytokines genes, endothelial growth factor and matrix metalloproteinases with the development of uterine fibroids among russian women

One of the factors in the development of uterine fibroids is a genetic predisposition to its occurrence in some women, but the real molecular genetic mechanisms of this phenomenon remain unknown. Aim of the study was the distribution analysis of gene polymorphism of cytokines TNFα, IL-1β, IL-4, IL-6, IL-10, factors of angiogenesis (vascular endothelial growth factor, VEGF) and remodeling of extracellular matrix (metalloproteinases MMP2, MMP3, MMP9), which are associated with their levels. Material and methods. Genotyping was performed by real-time PCR using commercial test systems SYBR GreenI (Litech, Russia) and TaqMan (Syntol, Russia) in accordance with the instructions of the developer. Cytokine content in blood serum was determined by flow cytometry using microspheres coated with monoclonal antibodies to cytokines (Bio-Plex ProTM Human Cytokine 27-plex Assay), according to the instructions for Bio-Plex 200 (Bio-Rad Laboratories, USA).To evaluate the results obtained, in addition to the generally accepted methods of statistical processing for case – control studies, computational methods of bioinformatics were used for comparative analysis of the diagnostic value of various combined genetic traits. Results. It was shown that the maximum odds ratio value of uterine fibroids development are combined genetic traits that include representatives of all four regulatory factors: cytokines with pro-inflammatory activity, cytokines with anti-inflammatory activity, vascular endothelial growth factors and metalloproteinases (p = 0.002). Conclusions. The presented data reveal the real mechanisms of manifestation of the genetic predisposition of individual women to the uterine fibroids development, associated with the presence of polymorphism of certain genes in their genome, which provide features of the structure of cytokine networks with the predominance of certain activities in the regulation of tissue processes in the uterus. In addition to purely scientific interest, these results indicate the real possibility of their clinical application in the form of prognostic criteria with a certain level of prognostic significance.

1. Aganezova N.V., Aganezov S.S., Shilo M.M. Uterine fibroids: modern practical aspects of the disease. Problemy reproduktsii = Russian Journal of Human Reproduction. 2022;28(4):97–105. [In Russian]. doi: 10.17116/repro20222804197

2. Buianova S.N., Iudina N.V., Gukasian S.A., Mgeliashvili M.V. Uterine myoma growth: Current aspects. Rossiyskiy vestnik akushera-ginekologa = Russian Bulletin of Obstetrician-Gynecologist. 2012;12(4):42–48. [In Russian].

3. Svirepova K.A., Kuznetsova M.V., Sogoyan N.S., Zelensky D.V., Lolomadze E.A., Mikhailovskaya G.V., Mishina N.D., Donnikov A.E., Trofimov D.Yu. Hereditary risk factors for uterine leiomyoma: a search for marker SNPs. Vestnik Rossiyskogo gosudarstvennogo meditsinskogo universiteta = Bulletin of the Russian State Medical University. 2020; (1):27–33. [In Russian]. doi: 10.24075/vrgmu.2020.011

4. Ponomarenko I., Reshetnikov E., Polonikov A., Verzilina I., Sorokina I., Yermachenko A., Dvornyk V., Churnosov M. Candidate genes for age at menarche are associated with uterine leiomyoma. Front. Genet. 2021;11:512940. doi: 10.3389/fgene.2020.512940

5. Kuznetsova М.V., Sogoyan N.S., Donnikov A.J., Trofimov D.Y., Adamyan L.V., Mishina N.D., Shubina J., Zelensky D.V., Sukhikh G.T. Familial predisposition to leiomyomata: searching for protective genetic factors affiliations expand. Biomedicines. 2022;10(2):508–520. doi: 10.3390/biomedicines10020508

6. Konenkov V.I., Koroleva E.G., Orlov N.B., Prokof’ev V.F., Shevchenko A.V., Novikov A.M., Dergacheva T.I., Ostanin A.A. Anti-inflammatory activity of serum cytokines (IL-4, IL-10, IL-13) and the natural IL-1β receptor antagonist (IL-1RA) in women with uterine myoma. Akusherstvo i ginekologiya = Obstetrics and Gynecology. 2018;(10):80–85. [In Russian]. doi: 10.18565/aig.2018.10.80-85

7. Konenkov V.I., Koroleva E.G., Orlov N.B., Prokofyev V.F., Shevchenko A.V., Novikov A.M., Dergacheva T.I. Changes in the serum concentrations of CCL chemokines (MCP-1, MIP-1A, MIP-1Β, RANTES and EOTAXIN) in women with uterine myoma. Akusherstvo i ginekologiya = Obstetrics and Gynecology. 2019;(8):107–111. [In Russian]. doi: 10.18565/aig.2019.8.107-111

8. Konenkov V.I., Koroleva E.G., Orlov N.B., Prokof’ev V.F., Shevchenko A.V., Novikov A.M., Dergacheva T.I. Blood serum levels of proinflammatory cytokines (IL-1β, IL-6, TNFα, IL-8, IL-12P70, and IFNγ) in patients with uterine myoma. Bull. Exp. Biol. Med. 2018;165:698–701.

9. Konenkov V.I., Koroleva E.G., Orlov N.B., Prokofiev V.F., Shevchenko A.V., Novikov A.M. Serum levels of hemopoietic and angiogenesis growth factors (IL-5, IL-7, IL-9, FGF-β, G-CSF, VEGF AND PDGF) in women with uterine myoma. Meditsinskaya immunologiya = Medical Immunology. 2018;20(5):691–698. [In Russian]. doi: 10.15789/1563-0625-2018-5-691-698

10. Kolchanov N.A., Ignatieva E.V., Podkolodnaya O.A., Likhoshvai V.A., Matushkin Yu.G. Gene networks. Vavilovskiy zhurnal genetiki i selektsii = Vavilov Journal of Genetics and Breeding. 2013;17(4/2):833– 850. [In Russian].

11. Weir B.S. Genetic data analysis: Method for discrete population genetic data. Moscow: Mir, 1995. 400 p. [In Russian].

12. Glantz S. Medico-biological statistics. Moscow: Praktika, 1998. 459 p. [In Russian].

13. Pietrowski D., Thewes R., Sator M., Denschlag D., Keck C., Tempfer C. Uterine leiomyoma is associated with a polymorphism in the interleukin 1-beta gene. Am. J. Reprod. Immunol. 2009;62(2):112– 117. doi: 10.1111/j.1600-0897.2009.00718.x

14. Hsieh Y.Y., Chang C.C., Tsai F.J., Lin C.C., Tsai C.H. T allele for VEGF-460 gene polymorphism at 5’-untranslated region is associated with higher susceptibility of leiomyoma. Biochem. Genet. 2008;46(5- 6):356–361. doi: 10.1007/s10528-008-9150-1

15. Sosna O., Kolesár L., Slavčev A., Skibová J., Fait T., Mara M., Stříž I., Kužel D. Th1/Th2 cytokine gene polymorphisms in patients with uterine fibroid. Folia Biol. (Praha). 2010;56(5):206–210.

16. Savchenko I.N., Garbuzova V.Yu. Role of single-nucleotide polymorphism C-1562т of the matrix metaloproteіnaza-9 gene in the development of leiomyoma in women with cervical pathology. Georgian Med. News. 2015;239(2):18–22. [In Russian].