Polymorphism of genes affecting remodeling of connective tissue, in patients with infertility

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The aim of the study was to evaluate the association of gene polymorphism of matrix metalloproteinase 2 (MMP2), MMP3, MMP9, urokinase plasminogen activator (PLAU) and transforming growth factor β1 (TGF-β1) with the occurrence of infertility.

Material and methods. 84 women planning pregnancy were examined. Of these, 47 did not become pregnant in six months (the first group), 37 had a pregnancy, and lasted more than 22 weeks (second group). The single-nucleotide polymorphisms (SNPs) of rs2285052 and rs243865 of the MMP2 gene, rs3025058 of the MMP3 gene, rs17576 and rs3918242 of the MMP9 gene, rs4065 and rs2227564 of the PLAU gene, rs1800469 of the TGF gene were analyzed in all patients. Statistical analysis of genetic associations was carried out using the SNPStats program.

Results. Patients with the A allele rs2285052 and the T allele rs243865 of the MMP2 gene had an increased risk of infertility (for rs2285052 in the group of patients without pregnancy, СС 27.7%, AС 51.1%, AA 21.3%; in the pregnant group СС 54%, AС 40.5%, AA 5.4%; for rs 243865 in the group of patients without pregnancy СС 57.5%, CT 40.4%, TT 2.1%; in the pregnant group СС 81.1%, CT 18, 9%, TT 0%). With the log-additive variant of inheritance, the OR (95% CI) was 0.38 (0.19–0.77) (p = 0.0043) for rs2285052 and 0.32 (0.12–0.84) (p = 0.015) for rs243865.

No statistically significant differences were found between the main group and the comparison group in allele frequencies rs3025058 of the MMP3 gene, rs17576 and rs3918242 of the MMP9 gene, rs4065 and rs2227564 of the PLAU gene, rs1800469 of the TGF-β1 gene.

Conclusions. In the studied sample of patients SNPs rs2285052 and rs243865 of the MMP2 gene were associated with a risk of infertility: the presence of the A allele rs2285052 and the T allele rs243865 of the MMP2 gene were associated with an increased risk of infertility.

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About the authors

Tat’yana E. Filipenkova

Center of Family Planning and Reproduction of the Moscow Department of Health

Author for correspondence.
Email: arvensa@list.ru
ORCID iD: 0000-0003-1443-8671

Russian Federation, Moscow

Center of Family Planning and Reproduction of the Moscow Department of Health

Liya N. Shcherbakova

Center of Family Planning and Reproduction of the Moscow Department of Health; Lomonosov Moscow State University

Email: liya.fbm@gmail.com
ORCID iD: 0000-0003-2681-4777

Russian Federation, Moscow

MD, Ph.D.

Aleksandr V. Balatskiy

Lomonosov Moscow State University; National Medical Research Center of Cardiology

Email: balatsky@fbm.msu.ru
ORCID iD: 0000-0002-6694-2231

Russian Federation, Moscow

MD, Ph.D.

Larisa M. Samokhodskaya

Lomonosov Moscow State University

Email: slm61@mail.ru
ORCID iD: 0000-0001-6734-3989

Russian Federation, Moscow

MD, Ph.D.

Mariya V. Alekseyenkova

Center of Family Planning and Reproduction of the Moscow Department of Health; Lomonosov Moscow State University

Email: m.alexeenkova@gmail.com
ORCID iD: 0000-0003-1910-6940

Russian Federation, Moscow

MD, Ph.D.

Ol’ga B. Panina

Center of Family Planning and Reproduction of the Moscow Department of Health; Lomonosov Moscow State University

Email: olgapanina@yandex.ru
ORCID iD: 0000-0003-1397-6208

Russian Federation, Moscow

MD, Ph.D., Professor


  1. Collins J.A., Van Steirteghem A. Overall prognosis with current treatment of infertility. Hum. Reprod. Update. 2004;10(4):309-16.
  2. Belokurova M.V., Samokhodskaya L.M., Kramarenko M.P., Sadekоva O.N., Panina O.B., Savel’yeva G.M. et al. Allele gene polimorphism of angiogenesis factors at patients with repeated IVF failure. Vestnik RUDN. 2012;5:62-6. (In Russ.)
  3. Abdul-Muneer P.M., Pfister B.J., Haorah J., Chandra N. Role of matrix metalloproteinases in the pathogenesis of traumatic brain injury. Mol. Neurobiol. 2016;53:6106-23.
  4. Sakowicz A., Lisowska M., Biesiada L., Rybak-Krzyszkowska M., Gach A., Sakowicz B., et al. Association of maternal and fetal single-nucleotide polymorphisms in metalloproteinase (MMP1, MMP2, MMP3, and MMP9) genes with preeclampsia. Dis. Markers. 2018; 2018:1371425.
  5. Huang X., Ye Q., Zhang Z., Huang X., Zhu Z., Chen Y., et al. Association of matrix metalloproteinase-3 gene 5A/6A polymorphism with the recurrence of ischemic stroke: A prospective observational study. Brain Res. 2017;1674:55-61.
  6. Yarmolinskaya M.I., Molotkov A.S., Bezhenar’ V.F., Shved N.Yu., Ivashchenko T.E., Baranov V.S. Association of matrix metalloproteinases' polymorphisms of MMP3 and MMP9 with development of genital endometriosis. Genetika. 2014;50(2):230-5. (In Russ.)
  7. Li L., Liu J., Qin S., Li R. The association of polymorphisms in promoter region of MMP2 and MMP9 with recurrent spontaneous abortion risk in Chinese population. Medicine (Baltimore). 2018;97(40): e12561.
  8. Parfenova E.V., Plekhanova O.S., Men’shikov M.Y., Stepanova V.V., Tkachuk V.A. Regulation of growth and remodeling of blood vessels: the unique role of urokinase. Rossiyskiy Fiziologicheskiy Zhurnal imeni I.M. Sechenova. 2009;95(5):442-64. (In Russ.)
  9. Katsuda S., Okada Y., Okada Y., Imai K., Nakanishi I. Matrix metalloproteinase-9 (92-kd gelatinase/type IV collagenase equals gelatinase B) can degrade arterial elastin. Am. J. Pathol. 1994;145(5):1208-18.
  10. Xu J., Li W., Bao X., Ding H., Chen J., Zhang W. et al. Association of putative functional variants in the PLAU gene and the PLAUR gene with myocardial infarction. Clin. Sci. (Lond). 2010;119(8):353-9.
  11. Duran J., Sánchez-Olavarría P., Mola M., Götzens V., Carballo J., Martín-Pelegrina E. et al. The PLAU P141L single nucleotide polymorphism is associated with collateral circulation in patients with coronary artery disease. Rev. Esp. Cardiol. (Engl. Ed). 2014;67(7): 552-7.
  12. Zhong F., Yang X.C., Bu L.X., Li N.Y., Chen W.T. Single nucleotide polymorphisms in the u-PA gene are related to susceptibility to oral tongue squamous cell carcinoma in the northern Chinese Han population. Asian Pac. J. Cancer Prev. 2013;14:781-4.
  13. Bowen J.M., Chamley L., Mitchell M.D., Keelan J.A. Cytokines of the placenta and extra-placental membranes: biosynthesis, secretion and roles in establishment of pregnancy in women. Placenta. 2002; 23:239-56.
  14. Bischof P., Meisser A., Campana A. Mechanisms of endometrial control of trophoblast invasion. J. Reprod. Fertil. Suppl. 2000;55:65-71.
  15. Du L., Gong T., Yao M., Dai H., Ren H.G., Wang H. Contribution of the polymorphism rs1800469 of transforming growth factor β in the development of myocardial infarction: meta-analysis of 5460 cases and 8413 controls (MOOSE-compliant article). Medicine (Baltimore). 2019;98(26):e15946.
  16. Chen J., Tan W., Wang D., Zhao L., Gao H., Zhang N., Wang C. Association of Foxp3 and TGF-β1 polymorphisms with pre-eclampsia risk in Chinese women. Genet. Test Mol. Biomarkers. 2019; 23(3):180-7.
  17. Yang L., Wang Y.J., Zheng L.Y., Jia Y.M., Chen Y.L., Chen L. et al. Genetic Polymorphisms of TGFB1, TGFBR1, SNAI1 and TWIST1 are associated with endometrial cancer susceptibility in Chinese Han women. PLoS One. 2016;11(5):e0155270.
  18. Agarkova T.A., Kublinskiy K.S., Men’shikova N.S., Naslednikova I.O., Evtushenko I.D., Agarkova L.A. et al. Polymorphism of the cytokines genes in endometriosis associated infertility. Fundamental’nyye issledovaniya. 2012;8(2):265-70. (In Russ.)
  19. Roh E.Y., Yoon J.H., Song E.Y., Kim J.J., Hwang K.R., Seo S.H., Shin S. Single nucleotide polymorphisms in the TGF-β1 gene are associated with polycystic ovary syndrome susceptibility and characteristics: a study in Korean women. J. Assist. Reprod. Genet. 2017; 34(1):139-47.
  20. Sole X., Guino E., Valls J. Iniesta R., Moreno V. SNPStats: a web tool for the analysis of association studies. Bioinformatics. 2006; 22(15):1928-9.
  21. Salamonsen L.A. Role of proteases in implantation. Rev. Reprod. 1999;4(1):11-22.
  22. Jokimaa V., Oksjoki S., Kujari H., Vuorio E., Anttila L. Altered expression of genes involved in the production and degradation of endometrial extracellular matrix in patients with unexplained infertility and recurrent miscarriages. Hum. Reprod. 2004;8:1111-6.
  23. O'Reilly M.S., Wiederschain D., Stetler-Stevenson W.G., Folkman J., Moses M.A. Regulation of angiostatin production by matrix metalloproteinase-2 in a model of concomitant resistance. J. Biol. Chem. 1999;274(41):29568-71.
  24. Fernandez-Patron C., Martinez-Cuesta M.A., Salas E., Sawicki G., Wozniak M., Radomski M.W. et al. Differential regulation of platelet aggregation by matrix metalloproteinase-9 and -2. Thromb. Haemost. 1999;82:1730-5.
  25. Parks W.C., Wilson C.L., Lopez-Boado Y.S. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat. Rev. Immunol. 2004;4:617-29.
  26. Hulboy D.L., Rudolph L.A., Matrisian L.M. Matrix metalloproteinases as mediators of reproductive function. Mol. Hum. Reprod. 1997; 3:27-45.
  27. Price S.J., Greaves D.R., Watkins H. Identification of novel, functional genetic variants in the human matrix metalloproteinase-2 gene: role of Sp1 in allele-specific transcriptional regulation. J. Biol. Chem. 2001;276(10):7549-58.
  28. Borghese B., Chiche J.D., Vernerey D., Chenot C., Mir O., Bijaoui G. et al. Genetic polymorphisms of matrix metalloproteinase 12 and 13 genes are implicated in endometriosis progression. Hum. Reprod. 2008;23(5):1207-13.
  29. Xu E., Xia X., Lu B., Xing X., Huang Q., Ma Y. et al. Association of matrix metalloproteinase-2 and -9 promoter polymorphisms with colorectal cancer in Chinese. Mol. Carcinog. 2007;46(11):924-9.



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