2658-6533Research Results in Biomedicine2658-653310.18413/2658-6533-2024-10-4-0-43592Genetics<strong>Characteristics of inter-locus interactions in the development of isolated and combined complications of pregnancy</strong><br /> &nbsp;<strong>Characteristics of inter-locus interactions in the development of isolated and combined complications of pregnancy</strong><br /> &nbsp;GolovchenkoOleg V.GolovchenkoOleg V.gol.doc@mail.ru202410400

Background: Pregnancy complications have a high prevalence and important medical and social implications. Genetic factors are involved in their development. The aim of the study: To study the characteristics of interlocus interactions in the formation of isolated and combined pregnancy complications. Materials and methods: The sample for the study consisted of 786 pregnant women, including 462 women were with various pregnancy complications (isolated preeclampsia (PE) (n=190); 2) isolated fetal growth retardation (FGR) (n=196); 3) a combination of PE and FGR (n=76)) and 324 women with a physiological course of pregnancy. Genotyping was performed for 13 polymorphic loci of growth factor genes and their receptors (rs4444903 EGF, rs833061 VEGFA, rs2981582 FGFR2, rs6214 IGF1, rs1800469 TGF&szlig;1), estrogen and progesterone receptor genes (rs2234693 ESR1, rs9340799 ESR1, rs3798577 ESR1, rs484389 PGR, rs1042838 PGR) and hereditary thrombophilia genes (rs1126643 ITGA2, rs5918 ITGB3 and rs5985 F13A1). The interaction of polymorphic loci associated with the studied pregnancy complications, visualization and determination of the nature (synergism, independent effect, antagonism) and strength (proportion of contribution to the entropy of the trait) of these interactions were studied using MB-MDR and MDR methods. Results: The risk of developing isolated FGR is determined by three models of interlocus interactions of 5 polymorphisms: rs4444903 EGF, rs6214 IGF1, rs2234693 ESR1, rs484389 PGR and rs5985 F13A1 with the most pronounced effects of the polymorphic locus rs6214 IGF1. Susceptibility to isolated PE is determined by the interlocus interactions of five loci: rs4444903 EGF, rs833061 VEGFA, rs2981582 FGFR2, rs2234693 ESR1, rs9340799 ESR1, in which the two-locus interaction rs9340799 ESR1xrs2234693 ESR1 plays a key role (it is part of all 3 models). The formation of a combination of FGR and PE is associated with two models of intergenic interactions of 4 polymorphisms: rs2234693 ESR1, rs9340799 ESR1, rs484389 PGR, rs5918 ITGB3. Three high-risk genotype combinations of genotypes showed the highest level of statistical significance of associations (p&lt;0.005) with pregnancy complications: TT-rs2234693 ESR1xGA-rs6214 IGF1 &ndash; isolated FGR (&beta; = 1.86, p=0.003); AA-rs9340799 ESR1xTT-rs2234693 ESR1 &ndash; isolated PE (&beta; = 2.45, p=0.0009) and the combination of PE and FGR (&beta; = 2.38, p=0.002). Conclusion: The risk of pregnancy complications is largely determined by the genetic combinatorics of the three polymorphic loci rs2234693 ESR1, rs9340799 ESR1, rs6214 IGF1

Background: Pregnancy complications have a high prevalence and important medical and social implications. Genetic factors are involved in their development. The aim of the study: To study the characteristics of interlocus interactions in the formation of isolated and combined pregnancy complications. Materials and methods: The sample for the study consisted of 786 pregnant women, including 462 women were with various pregnancy complications (isolated preeclampsia (PE) (n=190); 2) isolated fetal growth retardation (FGR) (n=196); 3) a combination of PE and FGR (n=76)) and 324 women with a physiological course of pregnancy. Genotyping was performed for 13 polymorphic loci of growth factor genes and their receptors (rs4444903 EGF, rs833061 VEGFA, rs2981582 FGFR2, rs6214 IGF1, rs1800469 TGF&szlig;1), estrogen and progesterone receptor genes (rs2234693 ESR1, rs9340799 ESR1, rs3798577 ESR1, rs484389 PGR, rs1042838 PGR) and hereditary thrombophilia genes (rs1126643 ITGA2, rs5918 ITGB3 and rs5985 F13A1). The interaction of polymorphic loci associated with the studied pregnancy complications, visualization and determination of the nature (synergism, independent effect, antagonism) and strength (proportion of contribution to the entropy of the trait) of these interactions were studied using MB-MDR and MDR methods. Results: The risk of developing isolated FGR is determined by three models of interlocus interactions of 5 polymorphisms: rs4444903 EGF, rs6214 IGF1, rs2234693 ESR1, rs484389 PGR and rs5985 F13A1 with the most pronounced effects of the polymorphic locus rs6214 IGF1. Susceptibility to isolated PE is determined by the interlocus interactions of five loci: rs4444903 EGF, rs833061 VEGFA, rs2981582 FGFR2, rs2234693 ESR1, rs9340799 ESR1, in which the two-locus interaction rs9340799 ESR1xrs2234693 ESR1 plays a key role (it is part of all 3 models). The formation of a combination of FGR and PE is associated with two models of intergenic interactions of 4 polymorphisms: rs2234693 ESR1, rs9340799 ESR1, rs484389 PGR, rs5918 ITGB3. Three high-risk genotype combinations of genotypes showed the highest level of statistical significance of associations (p&lt;0.005) with pregnancy complications: TT-rs2234693 ESR1xGA-rs6214 IGF1 &ndash; isolated FGR (&beta; = 1.86, p=0.003); AA-rs9340799 ESR1xTT-rs2234693 ESR1 &ndash; isolated PE (&beta; = 2.45, p=0.0009) and the combination of PE and FGR (&beta; = 2.38, p=0.002). Conclusion: The risk of pregnancy complications is largely determined by the genetic combinatorics of the three polymorphic loci rs2234693 ESR1, rs9340799 ESR1, rs6214 IGF1

polymorphismassociationsSNP×SNP interactionspre-eclampsiafetal growth retardationpolymorphismassociationsSNP×SNP interactionspre-eclampsiafetal growth retardationСписок литературыSidorova IS, Unanyan AL, Nikitina NA, et al. Modern possibilities of prediction and early diagnosis of preeclampsia. Russian Bulletin of Obstetrician-Gynecologist. 2021;21(6):32‑43. Russian. DOI: https://doi.org/10.17116/rosakush20212106132Abramova MY, Churnosov MI. Modern concepts of etiology, pathogenesis and risk factors for preeclampsia. Journal of Obstetrics and Women&#39;s Diseases. 2021;70(5):105-116. Russian. DOI: https://doi.org/10.17816/JOWD77046Overton E, Tobes D, Lee A. Preeclampsia diagnosis and management. Best Practice and Research in Clinical Anaesthesiology. 2022;36(1):107-121. DOI: https://doi.org/10.1016/j.bpa.2022.02.003Khodzhaeva ZS, Oshkhunova MS, Muminova KT, et al. Prediction and early diagnosis of preeclampsia: scientific perspectives and clinical opportunities. Obstetrics and Gynecology. 2022;12:57-65. Russian. DOI: http://dx.doi.org/10.18565/aig.2022.218Erez O, Romero R, Jung E, et al. Preeclampsia and eclampsia: the conceptual evolution of a syndrome. American Journal of Obstetrics and Gynecology. 2022;226(2S):S786-S803. DOI: https://doi.org/10.1016/j.ajog.2021.12.001Roberts JM. Preeclampsia epidemiology(ies) and pathophysiology(ies). Best Practice and Research in Clinical Obstetrics and Gynaecology. 2024;94:102480. DOI: https://doi.org/10.1016/j.bpobgyn.2024.102480Martins JG, Biggio JR, Abuhamad A, et al. Society for Maternal-Fetal Medicine Consult Series #52: Diagnosis and management of fetal growth restriction: (Replaces Clinical Guideline Number 3, April 2012). American Journal of Obstetrics and Gynecology. 2020;223(4):B2-B17. DOI: https://doi.org/10.1016/j.ajog.2020.05.010Melamed N, Baschat A, Yinon Y, et al. FIGO (international Federation of Gynecology and obstetrics) initiative on fetal growth: best practice advice for screening, diagnosis, and management of fetal growth restriction. International Journal of Gynaecology and Obstetrics. 2021;152(Suppl 1):3-57. DOI: https://doi.org/10.1002/ijgo.13522Okladnikov SM, Nikitina SY, Aleksandrova GA, et al. editors. Zdravookhranenie v Rossii. 2023: Statistical Collection/Rosstat. Moscow: Rosstat; 2023. Russian.Reshetnikov E, Churnosova M, Reshetnikova Y, et al. Maternal Age at Menarche Genes Determines Fetal Growth Restriction Risk. International Journal of Molecular Sciences. 2024;25(5):2647. DOI: https://doi.org/10.3390/ijms25052647Churnosov M, Abramova M, Reshetnikov E, et al. Polymorphisms of hypertension susceptibility genes as risk factors of preeclampsia in the Caucasian population of central Russia. Placenta. 2022;129:51-61. DOI: https://doi.org/10.1016/j.placenta.2022.09.010Abramova MYu, Churnosov MI. Genetic studies of pre-eclampsia. Russian Bulletin of Obstetrician-Gynecologist. 2022;22(6):27‑34. Russian. DOI: https://doi.org/10.17116/rosakush20222206127Gray KJ, Kovacheva VP, Mirzakhani H, et al. Risk of pre-eclampsia in patients with a maternal genetic predisposition to common medical conditions: a case-control study. BJOG: An International Journal of Obstetrics and Gynaecology. 2021;128(1):55-65. DOI: https://doi.org/10.1111/1471-0528.16441Steinthorsdottir V, McGinnis R, Williams NO, et al. Genetic predisposition to hypertension is associated with pre-eclampsia in European and Central Asian women. Nature Communications. 2020;11(1):5976. DOI: https://doi.org/10.1038/s41467-020-19733-6Abramova MYu. Genetic markers of severe preeclampsia. Research Results in Biomedicine. 2022;8(3):305-316. Russian. DOI: https://doi.org/10.18413/2658-6533-2022-8-3-0-4Golovchenko OV. Molecular genetic determinants of pre-eclampsia. Research Results in Biomedicine. 2019;5(4):139-149. Russian. DOI: https://doi.org/10.18413/2658-6533-2019-5-4-0-11Peng C, Hu LP, Bu XF, et al. The genetics and clinical outcomes in 151 cases of fetal growth restriction: A Chinese single-center study. European Journal of Obstetrics, Gynecology and Reproductive Biology. 2024;298:128-134. DOI: https://doi.org/10.1016/j.ejogrb.2024.05.004Peng X, He D, Peng R, et al. Associations between IGFBP1 gene polymorphisms and the risk of preeclampsia and fetal growth restriction. Hypertension Research. 2023;46(9):2070-2084. DOI: https://doi.org/10.1038/s41440-023-01309-8Reshetnikov EA. Study of associations of candidate genes differentially expressing in the placenta with the development of placental insufficiency with fetal growth restriction. Research Results in Biomedicine. 2020;6(3):338-349. Russian. DOI: https://doi.org/10.18413/2658-6533-2020-6-3-0-5Reshetnikova YuN, Ponomarenko IV, Churnosov VI, et al. Genetic variant rs11568818 of matrix metalloproteinase MMP7 associated with newborn weight in pregnant women with fetal growth restriction. Research Results in Biomedicine. 2024;10(2):222-233. Russian. DOI: https://doi.org/10.18413/2658-6533-2024-10-2-0-4Ponomarenko IV, Polonikov AV, Churnosov MI. Association of ESR2 rs4986938 polymorphism with the development of endometrial hyperplasia. Obstetrics and Gynecology. 2019;4:66-72. Russian. DOI: https://dx.doi.org/10.18565/aig.2019.4.66-72Yarosh SL, Kokhtenko EV, Churnosov MI, et al. Joint effect of glutathione S-transferase genotypes and cigarette smoking on idiopathic male infertility. Andrologia. 2015;47(9):980-986. DOI: https://doi.org/10.1111/and.12367Ponomarenko IV. Using the method of Multifactor Dimensionality Reduction (MDR) and its modifications for analysis of gene-gene and gene-environment interactions in genetic-epidemiological studies (review). Research Results in Biomedicine. 2019;5(1):4-21. Russian. DOI: https://doi.org/10.18413/2313-8955-2019-5-1-0-1Golovchenko OV, Ponomarenko IV, Churnosov MI. Polymorphism of the maternal EGF gene is associated with the fetal growth retardation: a prospective comparative study. Gynecology. 2021;23(6):554-558. Russian. DOI: https://doi.org/10.26442/20795696.2021.6.201232Golovchenko O, Abramova M, Ponomarenko I, et al. Functionally significant polymorphisms of ESR1and PGR and risk of intrauterine growth restriction in population of Central Russia. European Journal of Obstetrics, Gynecology and Reproductive Biology. 2020;253:52-57. DOI: https://doi.org/10.1016/j.ejogrb.2020.07.045Golovchenko OV, Abramova MYu, Ponomarenko IV, et al. Analysis of associations of polymorphic loci of the PGR gene with the development of pre-eclampsia. Russian Journal of Human Reproduction. 2022;28(1):29‑35. Russian. DOI: https://doi.org/10.17116/repro20222801129Golovchenko OV, Abramova MYu, Ponomarenko IV, et al. Polymorphic loci of the ESR1 gene are associated with the risk of developing preeclampsia with fetal growth retardation. Obstetrics, Gynecology and Reproduction. 2020;14(6):583-591. Russian. DOI: https://doi.org/10.17749/2313-7347/ob.gyn.rep.2020.187Deroo BJ, Korach KS. Estrogen receptors and human disease. Journal of Clinical Investigation. 2006;116(3):561-570. DOI: https://doi.org/10.1172/JCI27987Rumi MAK, Singh P, Roby KF, et al. Defining the Role of Estrogen Receptor &beta; in the Regulation of Female Fertility. Endocrinology. 2017;158(7):2330-2343. DOI: https://doi.org/10.1210/en.2016-1916Vasquez YM, DeMayo FJ. Role of nuclear receptors in blastocyst implantation. Seminars in Cell and Developmental Biology. 2013;24(10-12):724-735. DOI: https://doi.org/10.1016/j.semcdb.2013.08.004Zhang S, Regnault TRH, Barker PL, et al. Placental adaptations in growth restriction. Nutrients. 2015;7(1):360-389. DOI: https://doi.org/10.3390/nu7010360Sferruzzi-Perri AN, Owens JA, Pringle KG, et al. The neglected role of insulin-like growth factors in the maternal circulation regulating fetal growth. Journal of Physiology. 2011;589(1):7-20. DOI: https://doi.org/10.1113/jphysiol.2010.198622Roos S, Lagerl&ouml;f O, Wennergren M, et al. Regulation of amino acid transporters by glucose and growth factors in cultured primary human trophoblast cells is mediated by mtor signalling. American Journal of Physiology - Cell Physiology. 2009;297(3):723-731. DOI: https://doi.org/10.1152/ajpcell.00191.2009Devaskar SU, Chu A. Intrauterine Growth Restriction: Hungry for an Answer. Physiology. 2016;31(2):131-146. DOI: https://doi.org/10.1152/physiol.00033.2015Dovzhikova IV, Andrievskaya IV. Estrogen receptors (review). Part 2. Bulletin Physiology and Pathology of Respiration. 2019;(73):125-133. Russian. DOI: https://doi.org/10.36604/1998-5029-2019-73-125-133Napso T, Yong HEJ, Lopez-Tello J, et al. The Role of Placental Hormones in Mediating Maternal Adaptations to Support Pregnancy and Lactation. Frontiers in Physiology. 2018;9:1091. DOI: https://doi.org/10.3389/fphys.2018.01091Molvarec A, Ver A, Fekete A, et al. Association between estrogen receptor alpha (ESR1) gene polymorphisms and severe preeclampsia. Hypertension Research. 2007;30:205-211. DOI: https://doi.org/10.1291/hypres.30.205Zhao G, Cai Y, Liu J, et al. Association between the estrogen receptor &alpha; gene polymorphisms rs2234693 and rs9340799 and severe and mild pre-eclampsia: a meta-analysis. Bioscience Reports. 2019;39(2):BSR20181548. DOI: https://doi.org/10.1042/BSR20181548&nbsp;