Associations between maternal matrix metalloproteinase gene polymorphisms and birth weight

DOI

https://dx.doi.org/10.18565/aig.2026.101

Reshetnikova Yu.N., Ponomarenko I.V., Churnosov M.I., Reshetnikov E.A.
Belgorod National Research University, Belgorod, Russia

Objective. To investigate the associations between maternal matrix metalloproteinase gene polymorphisms and birth weight.
Materials and methods. In a cohort of pregnant women (n=317), single-nucleotide polymorphisms (SNPs) in five genes encoding matrix metalloproteinases (MMPs) were investigated: rs1799750 [1G>2G] in MMP-1, rs243865 [C>T] in MMP-2, rs3025058 [6A>5A] in MMP-3, rs11568818 [T>C] in MMP-7, and rs17577 [G>A] in MMP-9.
Results. Analysis of the associations between SNPs and birth weight identified two loci associated with this phenotype: the 5A allele of rs3025058 in MMP-3 [allelic model (β=-0.112, p=0.002, p_perm=0.003), additive model (β=-0.125, p=0.001, p_perm=0.001), dominant model (β=0.155, p=0.009, p_perm=0.013), and recessive model (β=-0.194, p=0.002, p_perm=0.002)] and the 2G allele of rs1799750 in MMP-1 [recessive model (β=0.153, p=0.015, p_perm=0.018)]. The polymorphic loci associated with birth weight exert functional effects in various organs and tissues involved in determining birth weight. The 2G allele of rs1799750 in MMP-1 is associated with lower MMP-1 gene expression in fibroblast cell cultures and in the thyroid gland, lungs, and visceral and subcutaneous adipose tissue. In addition, 35 SNPs in linkage disequilibrium with rs3025058 in MMP-3 (r2>0.8) also affect MMP-1 gene transcription in the thyroid gland, visceral adipose tissue, and fibroblast cell cultures.
Conclusion. Thus, the 5A allele of rs3025058 in MMP-3 is associated with lower birth weight, whereas the 2G allele of rs1799750 in MMP-1 is associated with higher birth weight.

Authors' contributions. Churnosov M.I., Reshetnikov E.A. – conception and design of the study, editing of the manuscript; Reshetnikova Yu.N. – data collection and processing, drafting of the manuscript; Ponomarenko I.V., Reshetnikova Yu.N. – statistical analysis. All authors have read and approved the final version of the manuscript.
Conflicts of interest. The authors have no conflicts of interest to declare.
Funding. There was no funding for this study.
Ethical Approval. The study was reviewed and approved by the Research Ethics Committee of the Medical Institute of BelSU (Protocol No. 2 dated February 13, 2008).
Generative Artificial Intelligence. No artificial intelligence tools were used in the preparation of this manuscript.
Patient Consent for Publication. All patients provided informed consent for the publication of their data.
Authors' Data Sharing Statement. The data supporting the findings of this study are available upon request from the corresponding author after approval from the principal investigator.
For citation: Reshetnikova Yu.N., Ponomarenko I.V., Churnosov M.I., Reshetnikov E.A.
Associations between maternal matrix metalloproteinase gene polymorphisms and birth weight.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2026; (9): 87-94 (in Russian)
https://dx.doi.org/10.18565/aig.2026.101

birth weight

matrix metalloproteinases

single-nucleotide polymorphism

associations

Full text (in Russian)

Zanetti D., Tikkanen E., Gustafsson S., Priest J.R., Burgess S., Ingelsson E. Birthweight, type 2 diabetes mellitus, and cardiovascular disease: addressing the barker hypothesis with mendelian randomization. Circ. Genom. Precis. Med. 2018; 11: e002054. https://dx.doi.org/10.1161/CIRCGEN.117.002054
Гуменюк Е.Г., Ившин А.А., Светова К.С. Задержка роста плода как предиктор здоровья на протяжении будущей жизни. Акушерство и гинекология. 2024; 3: 5-12. https://dx.doi.org/10.18565/aig.2023.277 [Gumeniuk E.G., Ivshin A.A., Svetova K.S. Fetal growth retardation as a predictor of health during the future life. Obstetrics and Gynecology. 2024; (3): 5-12 (in Russian). https://dx.doi.org/10.18565/aig.2023.277].
Волочаева М.В., Кан Н.Е., Тютюнник В.Л., Леонова А.А., Солдатова Е.Е., Рыжова К.О. Особенности постнатального развития детей с задержкой роста (катамнестическое исследование). Акушерство и гинекология. 2025; 3: 65-71. https://dx.doi.org/10.18565/aig.2025.32 [Volochaeva M.V., Kan N.E., Tyutyunnik V.L., Leonova A.A., Soldatova E.E., Ryzhova K.O. Postnatal development in children with growth restriction (follow-up study). Obstetrics and Gynecology. 2025; (3): 65-71 (in Russian). https://dx.doi.org/10.18565/aig.2025.32].
Bordaeva O.Y., Alayasa N.N.I., Zezerova Y.S., Milutina N.P., Derevyanchuk E.G., Shkurat T.P. Clinic-laboratory blood parameters and the contribution of renin-angiotensin system gene polymorphisms in pregnant women with preeclampsia. Research Results in Biomedicine. 2025; 11(2): 200-14. https://dx.doi.org/10.18413/2658-6533-2025-11-2-0-1
Солдатова Е.Е., Кан Н.Е., Тютюнник В.Л., Волочаева М.В. Задержка роста плода с позиции фетального программирования. Акушерство и гинекология. 2022; 8: 5-10. https://dx.doi.org/10.18565/aig.2022.8.5-10 [Soldatova E.E., Kan N.E., Tyutyunnik V.L., Volochaeva M.V. Fetal growth retardation in the context of fetal programming. Obstetrics and Gynecology. 2022; (8): 5-10 (in Russian). https://dx.doi.org/10.18565/aig.2022.8.5-10].
Головченко О.В. Молекулярно-генетические детерминанты преэклампсии. Научные результаты биомедицинских исследований. 2019; 5(4): 139-49. https://dx.doi.org/10.18413/2658-6533-2019-5-4-0-11 [Golovchenko O.V. Molecular genetic determinants of pre-eclampsia. Research Results in Biomedicine. 2019; 5(4): 139-49. (in Russian). https://dx.doi.org/10.18413/2658-6533-2019-5-4-0-11].
Абрамова М.Ю. Генетические маркеры тяжелого течения преэклампсии. Научные результаты биомедицинских исследований. 2022; 8(3): 305-16. https://dx.doi.org/10.18413/2658-6533-2022-8-3-0-4 [Abramova M.Yu. Genetic markers of severe preeclampsia. Research Results in Biomedicine. 2022; 8(3): 305-16 (in Russian). https://dx.doi.org/10.18413/2658-6533-2022-8-3-0-4].
D'Agostin M., Di Sipio Morgia C., Vento G., Nobile S. Long-term implications of fetal growth restriction. World. J. Clin. Cases. 2023; 11(3): 2855-63 https://dx.doi.org/10.12998/wjcc.v11.i13.2855
Ахмедов Ф.К., Рахматуллаева М.М., Якубова О.А. Влияние полиморфизмов генов цитокинов на риск развития преэклампсии. Научные результаты биомедицинских исследований. 2025; 11(4): 709-26. https://dx.doi.org/10.18413/2658-6533-2025-11-4-0-9 [Akhmedov F.K., Rakhmatullaeva M.M., Yakubova O.A. Effect of cytokine gene polymorphisms on the risk of preeclampsia. Research Results in Biomedicine. 2025; 11(4):709-26 (in Russian). https://dx.doi.org/10.18413/2658-6533-2025-11-4-0-9].
Cabral-Pacheco G.A., Garza-Veloz I., Castruita-De la Rosa C., Ramirez-Acuña J.M., Perez-Romero B.A., Guerrero-Rodriguez J.F. et al. The roles of matrix metalloproteinases and their inhibitors in human diseases. Int. J. Mol. Sci. 2020; 21(24): 9739. https://dx.doi.org/10.3390/ijms21249739
Wang X., Khalil R.A. Matrix metalloproteinases, vascular remodeling, and vascular disease. Adv. Pharmacol. 2018; 81: 241-30. https://dx.doi.org/10.1016/bs.apha.2017.08.002
Chen J., Khalil R.A. Matrix metalloproteinases in normal pregnancy and preeclampsia. Prog. Mol. Biol. Transl. Sci. 2017; 148: 87-165. https://dx.doi.org/10.1016/bs.pmbts.2017.04.001
Laronha H., Caldeira J. Structure and function of human matrix metalloproteinases. Cells. 2020; 9(5): 1076. https://dx.doi.org/10.3390/cells9051076
Su M.T., Tsai P.Y., Tsai H.L., Chen Y.C., Kuo P.L. miR-346 and miR-582-3p-regulated EG-VEGF expression and trophoblast invasion via matrix metalloproteinases 2 and 9. Biofactors. 2017; 43(2): 210-19. https://dx.doi.org/10.1002/biof.1325
Garcha D., Walker S.P., MacDonald T.M., Hyett J., Jellins J., Myers J.et al. Circulating syndecan-1 is reduced in pregnancies with poor fetal growth and its secretion regulated by matrix metalloproteinases and the mitochondria. Sci. Rep. 2021; 11(1): 16595. https://dx.doi.org/10.1038/s41598-021-96077-1
Şahin B., Soyer-Çalışkan C., Çelik S., Hatırnaz Ş., Tinelli A. Midregional pro-adrenomedullin and matrix metalloproteinase-2 levels in intrauterine growth restriction and small gestational age pregnancies: biochemical diagnostic difference. J. Matern. Fetal. Neonatal. Med. 2021; 34(12): 1999-2005. https://dx.doi.org/10.1080/14767058.2020.1846707
Pei J., Li Y., Min Z., Dong Q., Ruan J., Wu J. et al. MiR-590-3p and its targets VEGF, PIGF, and MMP9 in early, middle, and late pregnancy: their longitudinal changes and correlations with risk of fetal growth restriction. Ir. J. Med. Sci. 2022; 191(3): 1251-7. https://dx.doi.org/10.1007/s11845-021-02664-6
Laskowska M., Dymara-Konopka W., Szmit E., Ledwich-Kibicka D., Wróbel A. Matrix metalloproteinase-3 in preeclamptic and normotensive pregnancies complicated by fetal growth restriction. Heliyon. 2023; 9(7): e18105. https://dx.doi.org/10.1016/j.heliyon.2023.e18105
Sengar A., Agrawal N.R. Fetal MMP2 polymorphism and the risk of fetal growth restriction. Global Journal For Research Analysis. 2025; 14(6): 4-7. https://dx.doi.org/10.36106/gjra/8004245
Mărginean C.O., Mărginean C., Bănescu C., Meliţ L.E., Tripon F., Iancu M. The relationship between MMP9 and ADRA2A gene polymorphisms and mothers-newborns' nutritional status: an exploratory path model (STROBE compliant article). Pediatr. Res. 2019; 85(6): 822-9. https://dx.doi.org/10.1038/s41390-019-0347-2
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. https://dx.doi.org/10.1155/2018/1371425
Behforouz A., Dastgheib S.A., Abbasi H., Karimi-Zarchi M., Javaheri A., Hadadan A. et al. Association of MMP-2, MMP-3, and MMP-9 polymorphisms with susceptibility to recurrent pregnancy loss. Fetal and Pediatric Pathology. 2021; 40(5): 378-86. https://dx.doi.org/10.1080/15513815.2019.1710879
Wysocka U., Sakowicz A., Jakubowski L., Pinkier I., Rybak-Krzyszkowska M., Alaszewski W. et al. Association between idiopathic recurrent pregnancy loss and genetic polymorphisms in cytokine and matrix metalloproteinase genes. Ginekol. Pol. 2021 Apr 29. https://dx.doi.org/10.5603/GP.a2021.0089
Yan Y., Fang L., Li Y., Yu Y., Li Y., Cheng J.C. et al. Association of MMP2 and MMP9 gene polymorphisms with the recurrent spontaneous abortion: A meta-analysis. Gene. 2021; 767: 145173. https://dx.doi.org/10.1016/j.gene.2020.145173
Mrozikiewicz A.E., Kurzawińska G., Goździewicz-Szpera A., Potograbski M., Ożarowski M., Karpiński T.M. et al. Effects of TIMP1 rs4898 gene polymorphism on early-onset preeclampsia development and placenta weight. Diagnostics (Basel). 2022; 12(7): 1637. https://dx.doi.org/10.3390/diagnostics12071637
Kanehisa M., Furumichi M., Sato Y., Kawashima M., Ishiguro-Watanabe M. KEGG for taxonomy-based analysis of pathways and genomes. Nucleic Acids Res. 2023; 51(D1): D587-92. https://dx.doi.org/10.1093/nar/gkac963
Rothfels K., Milacic M., Matthews L., Haw R., Sevilla C., Gillespie M. et al. Using the Reactome Database. Curr. Protoc. 2023; 3(4): e722. https://dx.doi.org/10.1002/cpz1.722
Ward L.D., Kellis M. HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease. Nucleic Acids Res. 2016; 44(D1): D877-81. https://dx.doi.org/10.1093/nar/gkv1340
John M., Korte A., Grimm D.G. The benefits of permutation-based genome-wide association studies. J. Exp. Bot. 2024; 75(17): 5377-89. https://dx.doi.org/10.1093/jxb/erae280
Пономаренко И.В. Отбор полиморфных локусов для анализа ассоциаций при генетико-эпидемиологических исследованиях. Научный результат. Медицина и фармация. 2018; 4(2): 40-54. https://dx.doi.org/10.18413/2313-8955-2018-4-2-0-5 [Ponomarenko I.V. Selection of polymorphic loci for association analysis in genetic-epidemiological studies. Research Result. Medicine and Pharmacy. 2018; 4(2): 40-54 (in Russian). https://dx.doi.org/10.18413/2313-8955-2018-4-2-0-5].
Kumar A., Moulik N.R., Agrawal S. Folic acid, one-carbon metabolism & childhood cancer. Indian J. Med. Res. 2017; 146: 163-74. https://dx.doi.org/10.4103/ijmr.ijmr_275_15
GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science. 2020; 369: 1318-30. https://dx.doi.org/10.1126/science.aaz1776
Zhang Q.W. Association of the matrix metalloproteinase-3 polymorphisms rs679620 and rs3025058 with ischemic stroke risk: a meta-analysis. Neuropsychiatr. Dis. Treat. 2018; 14: 419-27. https://dx.doi.org/10.2147/NDT.S152256
Laronha H., Caldeira J. Structure and function of human matrix metalloproteinases. Cells. 2020; 9(5):1076. https://dx.doi.org/10.3390/cells9051076
Laskowska M. Altered maternal serum matrix metalloproteinases MMP-2, MMP-3, MMP-9, and MMP-13 in severe early- and late-onset preeclampsia. Biomed. Res. Int. 2017; 2017: 6432426. https://dx.doi.org/10.1155/2017/6432426
Huang X.Y., Han L.Y., Huang X.D., Guan C.H., Mao X.L., Ye Z.S. Association of matrix metalloproteinase-1 and matrix metalloproteinase-3 gene variants with ischemic stroke and its subtype. J. Stroke Cerebrovasc. Dis. 2017; 26(2): 368-75. https://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.09.034
Misra S., Talwar P., Kumar A., Kumar P., Sagar R., Vibha D. et al. Association between matrix metalloproteinase family gene polymorphisms and risk of ischemic stroke: A systematic review and meta-analysis of 29 studies. Gene. 2018; 672: 180-94. https://dx.doi.org/10.1016/j.gene.2018.06.027
Polonikov A., Rymarova L., Klyosova E., Volkova A., Azarova I., Bushueva O. et al. Matrix metalloproteinases as target genes for gene regulatory networks driving molecular and cellular pathways related to a multistep pathogenesis of cerebrovascular disease. J. Cell. Biochem. 2019; 120(10): 16467-82. https://dx.doi.org/10.1002/jcb.28815
Москаленко М.И., Полоников А.В., Сорокина И.Н., Якунченко Т.И., Крикун Е.Н., Пономаренко И.В. Генно-средовые взаимодействия полиморфных локусов ММР и ожирения при формировании артериальной гипертонии у женщин. Проблемы Эндокринологии. 2019; 65(6): 425-35. https://dx.doi.org/10.14341/probl10236 [Moskalenko M.I., Polonikov A.V., Sorokina I.N., Yakunchenko T.I., Krikun Y.N., Ponomarenko I.V. Gene-environment interactions between polymorphic loci of MMPs and obesity in essential hypertension in women. Problems of Endocrinology. 2020; 65(6):425-35 (in Russian). https://dx.doi.org/10.14341/probl10236].
Ghaffarzadeh A., Bagheri M., Khadem-Vatani K., Abdi Rad I. Association of MMP-1 (rs1799750)-1607 2G/2G and MMP-3 (rs3025058)-1612 6A/6A genotypes with coronary artery disease risk among Iranian Turks. J. Cardiovasc. Pharmacol. 2019; 74(5): 420-5. https://dx.doi.org/10.1097/FJC.0000000000000727
Espino Y.S.S., Flores-Pliego A., Espejel-Nuñez A., Medina-Bastidas D., Vadillo-Ortega F., Zaga-Clavellina V. et al. New insights into the role of matrix metalloproteinases in preeclampsia. Int. J. Mol. Sci. 2017; 18(7): 1448. https://dx.doi.org/10.3390/ijms18071448.
Nugent W.H., Mishra N., Strauss J.F 3rd., Walsh S.W. Matrix metalloproteinase 1 causes vasoconstriction and enhances vessel reactivity to angiotensin ii via protease-activated receptor 1. Reprod. Sci. 2016; 23(4): 542-8. https://dx.doi.org/10.1177/1933719115607998

Received 25.03.2026

Accepted 16.09.2026

Yuliya N. Reshetnikova, PhD student at the Department of Biomedical Disciplines, Belgorod State National Research University, 308015, Russia, Belgorod, Pobedy str., 85, +7(4722)30-13-83, resh_yul@mail.ru, https://orcid.org/0009-0004-6123-4086
Irina V. Ponomarenko, Dr. Med. Sci., Professor at the Department of Biomedical Disciplines, Belgorod State National Research University, 308015, Russia, Belgorod,
Pobedy str., 85, +7(4722)30-13-83, ponomarenko_i@bsuedu.ru, https://orcid.org/0000-0002-5652-0166
Mikhail I. Churnosov, Dr. Med. Sci., Professor, Head of the Department of Biomedical Disciplines, Belgorod State National Research University, 308015, Russia, Belgorod, Pobedy str., 85, +7(4722)30-13-83, churnosov@bsuedu.ru, https://orcid.org/0000-0003-1254-6134
Evgeny A. Reshetnikov, Dr. Bio. Sci., Professor at the Department of Biomedical Disciplines, Belgorod State National Research University, 308015, Russia, Belgorod,
Pobedy str., 85, +7(4722)30-13-83, reshetnikov@bsuedu.ru, https://orcid.org/0000-0002-5429-6666
Corresponding author: Evgeny A. Reshetnikov, reshetnikov@bsuedu.ru

Associations between maternal matrix metalloproteinase gene polymorphisms and birth weight

Reshetnikova Yu.N., Ponomarenko I.V., Churnosov M.I., Reshetnikov E.A.

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