2658-6533Research Results in Biomedicine2658-653310.18413/2658-6533-2022-8-3-0-42807Genetics<strong>Genetic markers of severe preeclampsia</strong><strong>Genetic markers of severe preeclampsia</strong>AbramovaMaria Yu.AbramovaMaria Yu.abramova_myu@bsu.edu.ru20228300

Background:&nbsp;In modern medicine, close attention is paid to the issues of reducing maternal morbidity and mortality, to the structure of which hypertensive disorders of gestation, especially preeclampsia, make a significant contribution. The complex pathomorphological mechanisms underlying the etiopathogenesis of this pregnancy complication occur long before the manifestation of pronounced clinical signs, which complicates the early diagnosis of preeclampsia and determines the relevance of the search for new preeclampsia-specific markers, including genetic ones. The aim of the study:&nbsp;To evaluate the associations of polymorphic markers of GWAS-significant candidate genes of hypertension with the development of severe preeclampsia. Materials and methods:&nbsp;The sample of women with moderate preeclampsia included 145 individuals, and the sample of women with severe preeclampsia included 72 patients. All subjects underwent genotyping of four polymorphic loci (rs8068318 TBX2, rs2681472 ATP2B1, rs4387287 OBFC1, rs1799945 HFE). The empirical distribution of genotypes and its correspondence to the theoretically expected one within the framework of the Hardy-Weinberg regularity are studied. Logistic regression analysis was carried out and associations of polymorphic loci with the development of severe and moderate preeclampsia were studied according to four genetic models, with the introduction of corrections for covariates. Results:&nbsp;It was found that rs8068318 of the TBX2 gene is associated with the development of severe preeclampsia in the framework of allelic (OR = 0.45; рperm = 0.004), additive (OR = 0.46; рperm = 0.002), dominant (OR = 0.42; рperm = 0.005) and recessive (OR = 0.22; рperm = 0.04) genetic models. The polymorphic locus rs8068318 of the TBX2 gene is localized in the region of hypersensitivity to DNase, the region of DNA regulatory motifs to four transcription factors, the region of histone tags marking enhancers and promoters in various organs and tissues, negatively regulates the expression of the TBX2-AS1 gene in adipose tissue and brain, the TBX2 gene in the thyroid gland, and is associated with the level of alternative splicing of TBX2-AS1 and RP11-332H18.5 genes in various tissues. Conclusion:&nbsp;The rs8068318 polymorphic marker of the TBX2 gene is associated with the development of severe preeclampsia in the population of the Central Chernozem region of the Russian Federation.

Background:&nbsp;In modern medicine, close attention is paid to the issues of reducing maternal morbidity and mortality, to the structure of which hypertensive disorders of gestation, especially preeclampsia, make a significant contribution. The complex pathomorphological mechanisms underlying the etiopathogenesis of this pregnancy complication occur long before the manifestation of pronounced clinical signs, which complicates the early diagnosis of preeclampsia and determines the relevance of the search for new preeclampsia-specific markers, including genetic ones. The aim of the study:&nbsp;To evaluate the associations of polymorphic markers of GWAS-significant candidate genes of hypertension with the development of severe preeclampsia. Materials and methods:&nbsp;The sample of women with moderate preeclampsia included 145 individuals, and the sample of women with severe preeclampsia included 72 patients. All subjects underwent genotyping of four polymorphic loci (rs8068318 TBX2, rs2681472 ATP2B1, rs4387287 OBFC1, rs1799945 HFE). The empirical distribution of genotypes and its correspondence to the theoretically expected one within the framework of the Hardy-Weinberg regularity are studied. Logistic regression analysis was carried out and associations of polymorphic loci with the development of severe and moderate preeclampsia were studied according to four genetic models, with the introduction of corrections for covariates. Results:&nbsp;It was found that rs8068318 of the TBX2 gene is associated with the development of severe preeclampsia in the framework of allelic (OR = 0.45; рperm = 0.004), additive (OR = 0.46; рperm = 0.002), dominant (OR = 0.42; рperm = 0.005) and recessive (OR = 0.22; рperm = 0.04) genetic models. The polymorphic locus rs8068318 of the TBX2 gene is localized in the region of hypersensitivity to DNase, the region of DNA regulatory motifs to four transcription factors, the region of histone tags marking enhancers and promoters in various organs and tissues, negatively regulates the expression of the TBX2-AS1 gene in adipose tissue and brain, the TBX2 gene in the thyroid gland, and is associated with the level of alternative splicing of TBX2-AS1 and RP11-332H18.5 genes in various tissues. Conclusion:&nbsp;The rs8068318 polymorphic marker of the TBX2 gene is associated with the development of severe preeclampsia in the population of the Central Chernozem region of the Russian Federation.

preeclampsiapolymorphic locusTBX2GWASpreeclampsiapolymorphic locusTBX2GWASСписок литературыAbramova 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/JOWD77046Bovee EME, Gulati M, Maas AHEM. Novel Cardiovascular Biomarkers Associated with Increased Cardiovascular Risk in Women With Prior Preeclampsia/HELLP Syndrome: A Narrative Review. European Cardiology Review. 2021;16:e36. DOI: https://doi.org/10.15420/ecr.2021.21&nbsp;Ives CW, Sinkey R, Rajapreyar I, et al. Preeclampsia-Pathophysiology and Clinical Presentations: JACC State-of-the-Art Review. Journal of the American College of Cardiology. 2020;76(14):1690-1702. DOI: https://doi.org/10.1016/j.jacc.2020.08.014Roberts JM, Rich-Edwards JW, McElrath TF, et al. Global Pregnancy Collaboration. Subtypes of Preeclampsia: Recognition and Determining Clinical Usefulness. Hypertension. 2021;77(5):1430-1441. DOI: https://doi.org/10.1161/HYPERTENSIONAHA.120.14781Wilkerson RG, Ogunbodede AC.&nbsp;Hypertensive Disorders of Pregnancy.&nbsp;Emergency Medicine Clinics of North America. 2019;37(2):301-316. DOI: https://doi.org/10.1016/j.emc.2019.01.008Syundyukova EG, Chulkov VS, Ryabikina MG. Preeclampsia: The Modern State of the Problem. Doctor.Ru. 2021;20(1):11-16. Russian. DOI: https://doi.org/10.31550/1727-2378-2021-20-1-11-16McLaughlin K, Snelgrove JW, Sienas LE, et al. Phenotype-Directed Management of Hypertension in Pregnancy. Journal of the American Heart Association. 2022;11(7):e023694. DOI: https://doi.org/10.1161/JAHA.121.023694Hauspurg A, Countouris ME, Catov JM. Hypertensive Disorders of Pregnancy and Future Maternal Health: How Can the Evidence Guide Postpartum Management? Current Hypertension Reports. 2019;21(12):96. DOI: https://doi.org/10.1007/s11906-019-0999-7Stepan H, Hund M, Andraczek T. Combining Biomarkers to Predict Pregnancy Complications and Redefine Preeclampsia: The Angiogenic-Placental Syndrome. Hypertension. 2020;75(4):918-926. DOI: https://doi.org/10.1161/HYPERTENSIONAHA.119.13763Burton GJ, Redman CW, Roberts JM, et al. Pre-eclampsia: pathophysiology and clinical implications. BMJ. 2019;366:l2381. DOI: https://doi.org/10.1136/bmj.l2381Reshetnikov EA. Polymorphism of genes associated with the age at menarche and the risk of complications of pregnancy in women in the Central Black Earth Region of Russia. Research Results in Biomedicine. 2021;7(2):132-142. Russian. DOI: https://doi.org/10.18413/2658-6533-2021-7-2-0-3Golovchenko OV, Abramova MY, Ponomarenko IV, et al. Locus rs833061 of the VEGF Gene in Pregnant Women with Preeclampsia Is Associated with Newborn Weight. Russian Journal of Genetics. 2022;57(9):1100-1105. DOI: https://doi.org/10.1134/S1022795421090039Wan JP, Wang H, Li CZ, et al. The common single-nucleotide polymorphism rs2681472 is associated with early-onset preeclampsia in Northern Han Chinese women. Reproductive Sciences. 2014;21(11):1423-1427. DOI: https://doi.org/10.1177/1933719114527354Hou B, Jia X, Deng Z, et al. Exploration of CYP21A2 and CYP17A1 polymorphisms and preeclampsia risk among Chinese Han population: a large-scale case-control study based on 5021 subjects. Human Genomics. 2020;14(1):33. DOI: https://doi.org/10.1186/s40246-020-00286-0Serebrova VN, Trifonova EA, Stepanov VA. Evolutionary-genetic analysis of the role of regulatory regions in CORO2A gene in the development of hereditary predisposition to preeclampsia in russian and yakut ethnic groups. Research Results in Biomedicine. 2018;4(3):38-48 Russian. DOI: https://doi.org/10.18413/2313-8955-2018-4-3-0-4Hypertensive disorders during pregnancy, childbirth and the postpartum period. Preeclampsia. Eclampsia. Clinical Guidelines (treatment protocol). Moscow. 2016. Russian.Yarosh 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.12367Polonikov A, Bykanova M, Ponomarenko I, et al. The contribution of CYP2C gene subfamily involved in epoxygenase pathway of arachidonic acids metabolism to hypertension susceptibility in Russian population.&nbsp;Clinical and Experimental Hypertension. 2017;39(4):306-311. DOI: https://doi.org/10.1080/10641963.2016.1246562Yarosh SL, Kokhtenko EV, Starodubova NI, et al. Smoking status modifies the relation between CYP1A1*2C gene polymorphism and idiopathic male infertility: the importance of gene-environment interaction analysis for genetic studies of the disease. Reproductive Sciences. 2013;20(11):1302-1307. DOI: https://doi.org/10.1177/1933719113483013Bushueva O, Solodilova M, Churnosov M, et al. The flavin-containing monooxygenase 3 gene and essential hypertension: The joint effect of polymorphism E158K and cigarette smoking on disease susceptibility. International Journal of Hypertension. 2014;2014: 712169. DOI: https://doi.org/10.1155/2014/712169Surendran P, Drenos F, Young R, et al. Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension. Nature Genetics. 2016;48(10):1151-1161. DOI: https://doi.org/10.1038/ng.3654Liu C, Kraja AT, Smith JA, et al. Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci. Nature Genetics. 2016;48(10):1162-1170. DOI: https://doi.org/10.1038/ng.3660Chambers JC, Zhang W, Lord GM, et al. Genetic loci influencing kidney function and chronic kidney disease. Nature Genetics. 2010;42(5):373-375. DOI: https://doi.org/10.1038/ng.566Takagi Y, Shimada K, Shimada S, et al. SPIB is a novel prognostic factor in diffuse large B-cell lymphoma that mediates apoptosis via the PI3K-AKT pathway. Cancer Science. 2016;107(9):1270-1280. DOI: https://doi.org/10.1111/cas.13001Chang F, Xing P, Song F, et al. The role of T-box genes in the tumorigenesis and progression of cancer. Oncology Letters. 2016;12(6):4305-4311. DOI: https://doi.org/10.3892/ol.2016.5296Cho GS, Park DS, Choi SC, et al. Tbx2 regulates anterior neural specification by repressing FGF signaling pathway. Developmental Biology. 2017;421(2):183-193. DOI: https://doi.org/10.1016/j.ydbio.2016.11.020L&uuml;dtke TH, Wojahn I, Kleppa MJ, et al. Combined genomic and proteomic approaches reveal DNA binding sites and interaction partners of TBX2 in the developing lung. Respiratory Research. 2021;22(1):85. DOI: https://doi.org/10.1186/s12931-021-01679-ySeya D, Ihara D, Shirai M, et al. A role of Hey2 transcription factor for right ventricle development through regulation of Tbx2-Mycn pathway during cardiac morphogenesis. Development Growth and Differentiation. 2021;63(1):82-92. DOI: https://doi.org/10.1111/dgd.12707Fernando F, Veenboer GJM, Oudijk MA, et al. TBX2, a Novel Regulator of Labour. Medicina. 2021;57(6):515. DOI: https://doi.org/10.3390/medicina57060515Enikeev AD, Komelkov AV, Akselrod ME, et al. Non-canonical activity of retinoic acid as a possible mechanism of retinoid resistance in cancer therapy. Russian Journal of Biotherapy. 2019;18(4):43-50. Russian. DOI: https://doi.org/10.17650/1726-9784-2019-18-4-43-50Hubert MA, Sherritt SL, Bachurski CJ, et al. Involvement of transcription factor NR2F2 in human trophoblast differentiation. PLoS ONE. 2010;5(2):e9417. DOI: https://doi.org/10.1371/journal.pone.0009417