medsovetМедицинский СоветMeditsinskiy sovet = Medical Council2079-701X2658-5790REMEDIUM GROUP Ltd.10.21518/ms2022-006medsovet-7273Research ArticleГИНЕКОЛОГИЯGYNECOLOGYГенетические маркеры риска развития задержки роста плода у беременных с преэклампсиейGenetic markers of the risk of fetal growth retardation in pregnant women with preeclampsiahttps://orcid.org/0000-0002-1406-2515АбрамоваМ. Ю.AbramovaM. Yu.

Абрамова Мария Юрьевна, аспирант кафедры медико-биологических дисциплин Медицинского института 

308015, Белгород, ул. Победы, д. 85

Maria Yu. Abramova, Postgraduate Student, Department of Biomedical Disciplines of the Medical Institute 

85, Pobedy St., Belgorod, 308015

abramova_myu@bsu.edu.ruhttps://orcid.org/0000-0002-5652-0166ПономаренкоИ. В.PonomarenkoI. V.

Пономаренко Ирина Васильевна, д.м.н., доцент, профессор кафедры медико-биологических дисциплин Медицинского института 

308015, Белгород, ул. Победы, д. 85

Irina V. Ponomarenko, Dr. Sci. (Med.), Associate Professor, Professor of the Department of Biomedical Disciplines of the Medical Institute 

85, Pobedy St., Belgorod, 308015

ponomarenko_i@bsu.edu.ruhttps://orcid.org/0000-0003-3882-9191ОрловаВ. С.OrlovaV. S.

Орлова Валентина Семеновна, д.м.н., профессор кафедры акушерства и гинекологии Медицинского института 

308015, Белгород, ул. Победы, д. 85

Valentina S. Orlova, Dr. Sci. (Med.), Professor, Department of Obstetrics and Gynecology of the Medical Institute 

85, Pobedy St., Belgorod, 308015

orlova@bsu.edu.ruhttps://orcid.org/0000-0003-0068-6586БатлуцкаяИ. В.BatlutskayaI. V.

Батлуцкая Ирина Витальевна, д.б.н., доцент, заведующая кафедрой биотехнологии и микробиологии 

308015, Белгород, ул. Победы, д. 85

Irina V. Batlutskaya, Dr. Sci. (Biol.), Associate Professor, Head of the Department of Biotechnology and Microbiology 

85, Pobedy St., Belgorod, 308015

bat@bsu.edu.ruhttps://orcid.org/0000-0003-4967-2556ЕфремоваО. А.EfremovaO. A.

Ефремова Ольга Алексеевна, д.м.н., доцент, заведующая кафедрой факультетской терапии Медицинского института 

308015, Белгород, ул. Победы, д. 85

Olga A. Efremova, Dr. Sci. (Med.), Associate Professor, Head of the Department of Faculty Therapy of the Medical Institute 

85, Pobedy St., Belgorod, 308015

efremova@bsu.edu.ruhttps://orcid.org/0000-0001-9438-4858СорокинаИ. Н.SorokinaI. N.

Сорокина Инна Николаевна, д.б.н., профессор кафедры медико-биологических дисциплин Медицинского института 

308015, Белгород, ул. Победы, д. 85

Inna N. Sorokina, Dr. Sci. (Biol.), Professor of the Department of Biomedical Disciplines of the Medical Institute 

85, Pobedy St., Belgorod, 308015

sorokina@bsu.edu.ruhttps://orcid.org/0000-0003-1254-6134ЧурносовМ. И.ChurnosovM. I.

Чурносов Михаил Иванович, д.м.н., профессор, заведующий кафедрой медико-биологических дисциплин Медицинского института 

308015, Белгород, ул. Победы, д. 85

Mikhail I. Churnosov, Dr. Sci. (Med.), Professor, Head of the Department of Biomedical Disciplines of the Medical Institute 

85, Pobedy St., Belgorod, 308015

churnosov@bsu.edu.ruБелгородский государственный национальный исследовательский университетРоссияBelgorod State National Research UniversityRussian Federation20232612202206150156Copyright © Абрамова М.Ю., Пономаренко И.В., Орлова В.С., Батлуцкая И.В., Ефремова О.А., Сорокина И.Н., Чурносов М.И., 20232023Абрамова М.Ю., Пономаренко И.В., Орлова В.С., Батлуцкая И.В., Ефремова О.А., Сорокина И.Н., Чурносов М.И.Abramova M.Y., Ponomarenko I.V., Orlova V.S., Batlutskaya I.V., Efremova O.A., Sorokina I.N., Churnosov M.I.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.med-sovet.pro/jour/article/view/7273

Введение. Преэклампсия (ПЭ) и задержка роста плода (ЗРП), основным механизмом возникновения которых является патология плаценты, непосредственно влияют на структуру как материнской, так и перинатальной заболеваемости и смертности, что предопределяет медико-социальную значимость изучения ПЭ и  ЗРП, особенно генетических предикторов развития данных осложнений гестации. Цель. Изучить вовлеченность полиморфизма GWAS-значимых генов – кандидатов артериальной гипертензии в формирование ЗРП у беременных с ПЭ. Материалы и методы. В выборки для исследования вошли 83 беременные с ПЭ в сочетании с ЗРП и 369 женщин с изолированной ПЭ, вошедшие в группу контроля. Всем женщинам проведено молекулярно-генетическое исследование четырех полиморфизмов: rs932764 PLCE1, rs167479 RGL3, rs633185 ARHGAP42, rs7302981 CERS5, изучена их связь с развитием ЗРП у беременных с ПЭ. Функциональные эффекты полиморфных маркеров, показавших значимые ассоциации с формированием ЗРП у беременных с ПЭ, рассмотрены с помощью международных биоинформатических проектов по функциональной геномике (HaploReg, GTExportal, PolyPhen-2). Результаты и обсуждение. Генотип AA локуса rs9327643 гена PLCE1 достоверно снижает риск формирования ЗРП у беременных с  ПЭ согласно рецессивной модели  (ОШ  = 0,37; p  = 0,01; pperm  = 0,01). Полиморфный вариант rs932764  гена PLCE1 расположен в области регуляторных мотивов ДНК к двум факторам транскрипции Hdx и Zic, локализован в регионе гистонового белка, кодирующего энхансеры H3K4me1 в головном мозге и ассоциирован с экспрессией гена HDAC1P1 в тканях мужских гонад. Выводы. Полиморфный локус rs9327643 гена PLCE1 ассоциирован с риском развития ЗРП у беременных с ПЭ.

Introduction. Preeclampsia (PE) and fetal growth retardation (FGR), the main mechanism of which is the pathology of the placenta, directly affect the structure of both maternal and perinatal morbidity and mortality, which determines the medical and social significance of the study of PE and FGR, especially genetic predictors of the development of these complications of gestation. Objective. To study the involvement of GWAS polymorphism of significant arterial hypertension candidate genes in the formation of FGR in pregnant women with PE. Materials and methods. The samples for the study included 83 pregnant women with PE in combination with FGR and 369 women with isolated PE who were included in the control group. All women underwent a molecular genetic study of four polymorphisms: rs932764 PLCE1, rs167479 RGL3, rs633185 ARHGAP42, rs7302981 CERS5, and studied their relationship with the development of FGR in pregnant women with PE. The functional effects of polymorphic markers, which showed significant associations with the  formation of  FGR in  pregnant women with PE, were examined using international bioinformatic projects on functional genomics (HaploReg, GTExportal, PolyPhen-2). Results and discussion. The AA genotype of the rs9327643 locus of the PLCE1 gene significantly reduces the risk of FGR formation in pregnant women with PE according to the recessive model (OR = 0.37; p = 0.01; pperm = 0.01). The rs932764 polymorphic variant of the PLCE1 gene is located in the region of regulatory DNA motifs for 2 Hdx and Zic transcription factors, localized in the region of histone protein encoding H3K4me1 enhancers in the brain and associated with the expression of the HDAC1P1 gene in male gonad tissues. Conclusions. The polymorphic locus rs9327643 of the PLCE1 gene is associated with the risk of developing FGR in pregnant women with PE.

преэклампсиязадержка роста плодаполиморфизмPLCE1факторы рискаpreeclampsiafetal growth retardationpolymorphismPLCE1risk factorsРабота выполнена при финансовой поддержке гранта Президента РФ «Изучение генетических факторов репродуктивного здоровья женщин» (МД3284.2022.1.4).The work was supported by the grant of the President of the Russian Federation “Study of the genetic factors of women’s reproductive health” (MD3284.2022.1.4).ReferencesPaauw N.D., Lely A.T. Cardiovascular Sequels During and After Preeclampsia. Adv Exp Med Biol. 2018;1065:455–470. https://doi.org/10.1007/978-3-319-77932-4_28.Paauw N.D., Lely A.T. Cardiovascular Sequels During and After Preeclampsia. Adv Exp Med Biol. 2018;1065:455–470. https://doi.org/10.1007/978-3-319-77932-4_28.Ma’ayeh M., Costantine M.M. Prevention of preeclampsia. Semin Fetal Neonatal Med. 2020;25(5):101123. https://doi.org/10.1016/j.siny.2020.101123.Ma’ayeh M., Costantine M.M. Prevention of preeclampsia. Semin Fetal Neonatal Med. 2020;25(5):101123. https://doi.org/10.1016/j.siny.2020.101123.Ashraf U.M., Hall D.L., Rawls A.Z., Alexander B.T. Epigenetic processes during preeclampsia and effects on fetal development and chronic health. Clin Sci (Lond). 2021;135(19):2307–2327. https://doi.org/10.1042/CS20190070.Ashraf U.M., Hall D.L., Rawls A.Z., Alexander B.T. Epigenetic processes during preeclampsia and effects on fetal development and chronic health. Clin Sci (Lond). 2021;135(19):2307–2327. https://doi.org/10.1042/CS20190070.Kesavan K., Devaskar S.U. Intrauterine Growth Restriction: Postnatal Monitoring and Outcomes. Pediatr Clin North Am. 2019;66(2):403–423. https://doi.org/10.1016/j.pcl.2018.12.009.Kesavan K., Devaskar S.U. Intrauterine Growth Restriction: Postnatal Monitoring and Outcomes. Pediatr Clin North Am. 2019;66(2):403–423. https://doi.org/10.1016/j.pcl.2018.12.009.Pels A., Beune I.M., van Wassenaer-Leemhuis A.G., Limpens J., Ganzevoort W. Early-onset fetal growth restriction: A systematic review on mortality and morbidity. Acta Obstet Gynecol Scand. 2020;99(2):153–166. https://doi.org/10.1111/aogs.13702.Pels A., Beune I.M., van Wassenaer-Leemhuis A.G., Limpens J., Ganzevoort W. Early-onset fetal growth restriction: A systematic review on mortality and morbidity. Acta Obstet Gynecol Scand. 2020;99(2):153–166. https://doi.org/10.1111/aogs.13702.Пономаренко И.В., Решетников Е.А., Полоников А.В., Чурносов М.И. Полиморфный локус rs314276 гена LIN28B ассоциирован с возрастом менархе у женщин Центрального Черноземья России. Акушерство и гинекология. 2019;(2):98–104. https://doi.org/10.18565/aig.2019.2.98-104.Ponomarenko I.V., Reshetnikov E.A., Polonikov A.V., Churnosov M.I. The polymorphic locus rs314276 of the LIN28B gene is associated with the age of menarche in women of the Central Black Earth Region of Russia. Akusherstvo i Ginekologiya (Russian Federation). 2019;(2):98–104. (In Russ.) http://doi.org/10.18565/aig.2019.2.98-104.Reshetnikov E., Zarudskaya O., Polonikov A., Bushueva O., Orlova V., Krikun E. et al. Genetic markers for inherited thrombophilia are associated with fetal growth retardation in the population of Central Russia. J Obstet Gynaecol Res. 2017;43(7):1139–1144. http://doi.org/10.1111/jog.13329.Reshetnikov E., Zarudskaya O., Polonikov A., Bushueva O., Orlova V., Krikun E. et al. Genetic markers for inherited thrombophilia are associated with fetal growth retardation in the population of Central Russia. J Obstet Gynaecol Res. 2017;43(7):1139–1144. http://doi.org/10.1111/jog.13329.Golovchenko O., Abramova M., Ponomarenko I., Reshetnikov E., Aristova I., Polonikov A. et al. Functionally significant polymorphisms of ESR1and PGR and risk of intrauterine growth restriction in population of Central Russia. Eur J Obstet Gynecol Reprod Biol. 2020;253:52–57. http://doi.org/10.1016/j.ejogrb.2020.07.045.Golovchenko O., Abramova M., Ponomarenko I., Reshetnikov E., Aristova I., Polonikov A. et al. Functionally significant polymorphisms of ESR1and PGR and risk of intrauterine growth restriction in population of Central Russia. Eur J Obstet Gynecol Reprod Biol. 2020;253:52–57. http://doi.org/10.1016/j.ejogrb.2020.07.045.Сереброва В.Н., Трифонова Е.А., Степанов В.А. Эволюционно-генетический анализ роли регуляторных участков гена CORO2A в формировании наследственной предрасположенности к преэклампсии у русских и якутов. Научные результаты биомедицинских исследований. 2018;4(3):38–48. http://doi.org/10.18413/2313-8955-2018-4-3-0-4.Serebrova V.N., Trifonova E.A., Stepanov V.A. 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. (In Russ.) http://doi.org/10.18413/2313-8955-2018-4-3-0-4.Пономаренко И.В., Полоников А.В., Чурносов М.И. Полиморфные локусы гена LHCGR ассоциированы с развитием лейомиомы матки. Акушерство и гинекология. 2018;(10):86–91. https://doi.org/10.18565/aig.2018.10.86-91.Ponomarenko I.V., Polonikov A.V., Churnosov M.I. The polymorphic loci of the LHCGR gene are associated with the development of uterine leiomyoma. Akusherstvo i Ginekologiya (Russian Federation). 2018;(10):86–91. (In Russ.) https://doi.org/10.18565/aig.2018.10.86-91.Ходжаева З.С., Шмаков Р.Г., Ярыгина Т.А., Холин А.М., Долгушина Н.В., Кан Н.Е. и др. Недостаточный рост плода, требующий предоставления медицинской помощи матери (задержка роста плода): клинические рекомендации. М.; 2022. 73 с. Режим доступа: https://cr.minzdrav.gov.ru/recomend/722_1.Khodzhaeva Z.S., Shmakov R.G., Yarygina T.A., Kholin A.M., Dolgushina N.V., Kan N.E. et al. Insufficient fetal growth requiring medical care for the mother (fetal growth retardation): clinical guidelines. Moscow; 2022. 73 p. (In Russ.) Available at: https://cr.minzdrav.gov.ru/recomend/722_1.Адамян Л.В., Артымук Н.В., Белокриницкая Т.Е., Беломестнов С.Р., Братищев И.В., Вученович Ю.Д. и др. Гипертензивные расстройства во время беременности, в родах и послеродовом периоде. Преэклампсия. Эклампсия: клинические рекомендации (протокол лечения). М.; 2016. 73 с. Режим доступа: http://zdrav.spb.ru/media/filebrowser/гипертензивные_расстройства_во_время_беременности.pdf.Adamyan L.V., Artymuk N.V., Belokrinitskaya T.E., Belomestnov S.R., Bratishchev I.V., Vuchenovich Yu.D. et al. Hypertensive disorders during pregnancy, childbirth and postpartum period. Preeclampsia. Eclampsia: clinical guidelines (treatment protocol). Moscow; 2016. 73 p. (In Russ.) Available at: http://zdrav.spb.ru/media/filebrowser/гипертензивные_расстройства_во_время_беременности.pdf.Ehret G.B., Munroe P.B., Rice K.M., Bochud M., Johnson A.D., Chasman D.I. et al. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature. 2011;478(7367):103–109. https://doi.org/10.1038/nature10405.Ehret G.B., Munroe P.B., Rice K.M., Bochud M., Johnson A.D., Chasman D.I. et al. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature. 2011;478(7367):103–109. https://doi.org/10.1038/nature10405.Ehret G.B., Ferreira T., Chasman D.I., Jackson A.U., Schmidt E.M., Johnson T. et al. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals. Nat Genet. 2016;48(10):1171–1184. https://doi.org/10.1038/ng.3667.Ehret G.B., Ferreira T., Chasman D.I., Jackson A.U., Schmidt E.M., Johnson T. et al. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals. Nat Genet. 2016;48(10):1171–1184. https://doi.org/10.1038/ng.3667.Hoffmann T.J., Ehret G.B., Nandakumar P., Ranatunga D., Schaefer C., Kwok P.Y. et al. Genome-wide association analyses using electronic health records identify new loci influencing blood pressure variation. Nat Genet. 2017;49(1):54–64. https://doi.org/10.1038/ng.3715.Hoffmann T.J., Ehret G.B., Nandakumar P., Ranatunga D., Schaefer C., Kwok P.Y. et al. Genome-wide association analyses using electronic health records identify new loci influencing blood pressure variation. Nat Genet. 2017;49(1):54–64. https://doi.org/10.1038/ng.3715.Liu C., Kraja A.T., Smith J.A., Brody J.A., Franceschini N., Bis J.C. et al. Metaanalysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci. Nat Genet. 2016;48(10):1162–1170. https://doi.org/10.1038/ng.3660.Liu C., Kraja A.T., Smith J.A., Brody J.A., Franceschini N., Bis J.C. et al. Metaanalysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci. Nat Genet. 2016;48(10):1162–1170. https://doi.org/10.1038/ng.3660.Surendran P., Drenos F., Young R., Warren H., Cook J.P., Manning A.K. et al. Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension. Nat Genet. 2016;48(10):1151–1161. https://doi.org/10.1038/ng.3654.Surendran P., Drenos F., Young R., Warren H., Cook J.P., Manning A.K. et al. Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension. Nat Genet. 2016;48(10):1151–1161. https://doi.org/10.1038/ng.3654.Wain L.V., Vaez A., Jansen R., Joehanes R., van der Most P.J., Erzurumluoglu A.M. et al. Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney. Hypertension. 2017;70(3):e4–e19. https://doi.org/10.1161/HYPERTENSIONAHA.117.09438.Wain L.V., Vaez A., Jansen R., Joehanes R., van der Most P.J., Erzurumluoglu A.M. et al. Novel Blood Pressure Locus and Gene Discovery Using GenomeWide Association Study and Expression Data Sets From Blood and the Kidney. Hypertension. 2017;70(3):e4–e19. https://doi.org/10.1161/HYPERTENSIONAHA.117.09438.Feitosa M.F., Kraja A.T., Chasman D.I., Sung Y.J., Winkler T.W., Ntalla I. et al. Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries. PLoS ONE. 2018;13(6):e0198166. https://doi.org/10.1371/journal.pone.0198166.Feitosa M.F., Kraja A.T., Chasman D.I., Sung Y.J., Winkler T.W., Ntalla I. et al. Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries. PLoS ONE. 2018;13(6):e0198166. https://doi.org/10.1371/journal.pone.0198166.Giri A., Hellwege J.N., Keaton J.M., Park J., Qiu C., Warren H.R. et al. Trans-ethnic association study of blood pressure determinants in over 750,000 individuals. Nat Genet. 2019;51(1):51–62. https://doi.org/10.1038/s41588-018-0303-9.Giri A., Hellwege J.N., Keaton J.M., Park J., Qiu C., Warren H.R. et al. Trans-ethnic association study of blood pressure determinants in over 750,000 individuals. Nat Genet. 2019;51(1):51–62. https://doi.org/10.1038/s41588-018-0303-9.Sung Y.J., Winkler T.W., de Las Fuentes L., Bentley A.R., Brown M.R., Kraja A.T. et al. A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. Am J Hum Genet. 2018;102(3):375–400. https://doi.org/10.1016/j.ajhg.2018.01.015.Sung Y.J., Winkler T.W., de Las Fuentes L., Bentley A.R., Brown M.R., Kraja A.T. et al. A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. Am J Hum Genet. 2018;102(3):375–400. https://doi.org/10.1016/j.ajhg.2018.01.015.Takeuchi F., Akiyama M., Matoba N., Katsuya T., Nakatochi M., Tabara Y. et al. Interethnic analyses of blood pressure loci in populations of East Asian and European descent. Nat Commun. 2018;9(1):5052. https://doi.org/10.1038/s41467-018-07345-0.Takeuchi F., Akiyama M., Matoba N., Katsuya T., Nakatochi M., Tabara Y. et al. Interethnic analyses of blood pressure loci in populations of East Asian and European descent. Nat Commun. 2018;9(1):5052. https://doi.org/10.1038/s41467-018-07345-0.Zhou W., Nielsen J.B., Fritsche L.G., Dey R., Gabrielsen M.E., Wolford B.N. et al. Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies. Nat Genet. 2018;50(9):1335–1341. https://doi.org/10.1038/s41588-018-0184-y.Zhou W., Nielsen J.B., Fritsche L.G., Dey R., Gabrielsen M.E., Wolford B.N. et al. Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies. Nat Genet. 2018;50(9):1335–1341. https://doi.org/10.1038/s41588-018-0184-y.German C.A., Sinsheimer J.S., Klimentidis Y.C., Zhou H., Zhou J.J. Ordered multinomial regression for genetic association analysis of ordinal phenotypes at Biobank scale. Genet Epidemiol. 2020;44(3):248–260. https://doi.org/10.1002/gepi.22276.German C.A., Sinsheimer J.S., Klimentidis Y.C., Zhou H., Zhou J.J. Ordered multinomial regression for genetic association analysis of ordinal phenotypes at Biobank scale. Genet Epidemiol. 2020;44(3):248–260. https://doi.org/10.1002/gepi.22276.Wu Y., Byrne E.M., Zheng Z., Kemper K.E., Yengo L., Mallett A.J. et al. Genome-wide association study of medication-use and associated disease in the UK Biobank. Nat Commun. 2019;10(1):1891. https://doi.org/10.1038/s41467-019-09572-5.Wu Y., Byrne E.M., Zheng Z., Kemper K.E., Yengo L., Mallett A.J. et al. Genome-wide association study of medication-use and associated disease in the UK Biobank. Nat Commun. 2019;10(1):1891. https://doi.org/10.1038/s41467-019-09572-5.Zhu Z., Wang X., Li X., Lin Y., Shen S., Liu C.L. et al. Genetic overlap of chronic obstructive pulmonary disease and cardiovascular diseaserelated traits: a large-scale genome-wide cross-trait analysis. Respir Res. 2019;20(1):64. https://doi.org/10.1186/s12931-019-1036-8.Zhu Z., Wang X., Li X., Lin Y., Shen S., Liu C.L. et al. Genetic overlap of chronic obstructive pulmonary disease and cardiovascular diseaserelated traits: a large-scale genome-wide cross-trait analysis. Respir Res. 2019;20(1):64. https://doi.org/10.1186/s12931-019-1036-8.Vuckovic D., Bao E.L., Akbari P., Lareau C.A., Mousas A., Jiang T. et al. The Polygenic and Monogenic Basis of Blood Traits and Diseases. Cell. 2020;182(5):1214–1231.e11. https://doi.org/10.1016/j.cell.2020.08.008.Vuckovic D., Bao E.L., Akbari P., Lareau C.A., Mousas A., Jiang T. et al. The Polygenic and Monogenic Basis of Blood Traits and Diseases. Cell. 2020;182(5):1214–1231.e11. https://doi.org/10.1016/j.cell.2020.08.008.Sakaue S., Kanai M., Tanigawa Y., Karjalainen J., Kurki M., Koshiba S. et al. A cross-population atlas of genetic associations for 220 human phenotypes. Nat Genet. 2021;53(10):1415–1424. https://doi.org/10.1038/s41588-021-00931-x.Sakaue S., Kanai M., Tanigawa Y., Karjalainen J., Kurki M., Koshiba S. et al. A cross-population atlas of genetic associations for 220 human phenotypes. Nat Genet. 2021;53(10):1415–1424. https://doi.org/10.1038/s41588-021-00931-x.Jeong H., Jin H.S., Kim S.S., Shin D. Identifying Interactions between Dietary Sodium, Potassium, Sodium-Potassium Ratios, and FGF5 rs16998073 Variants and Their Associated Risk for Hypertension in Korean Adults. Nutrients. 2020;12(7):2121. https://doi.org/10.3390/nu12072121.Jeong H., Jin H.S., Kim S.S., Shin D. Identifying Interactions between Dietary Sodium, Potassium, Sodium-Potassium Ratios, and FGF5 rs16998073 Variants and Their Associated Risk for Hypertension in Korean Adults. Nutrients. 2020;12(7):2121. https://doi.org/10.3390/nu12072121.Абрамова М.Ю. Генетические маркеры тяжелого течения преэклампсии. Научные результаты биомедицинских исследований. 2022;8(3):305–316. https://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):305–316. (In Russ.) https://doi.org/10.18413/2658-6533-2022-8-3-0-4.Пономаренко И.В., Полоников А.В., Чурносов М.И. Ассоциация полиморфизма ESR2 rs4986938 с развитием гиперплазии эндометрия. Акушерство и гинекология. 2019;(4):66–72. https://doi.org/10.18565/aig.2019.4.66-72.Ponomarenko I.V., Polonikov A.V., Churnosov M.I. Association of ESR2 rs4986938 polymorphism with the development of endometrial hyperplasia. Akusherstvo i Ginekologiya (Russian Federation). 2019;(4):66–72. (In Russ.) https://doi.org/10.18565/aig.2019.4.66-72.Muralidharan K., Van Camp M.M., Lyon A.M. Structure and regulation of phospholipase Cβ and ε at the membrane. Chem Phys Lipids. 2021;235:105050. https://doi.org/10.1016/j.chemphyslip.2021.105050.Muralidharan K., Van Camp M.M., Lyon A.M. Structure and regulation of phospholipase Cβ and ε at the membrane. Chem Phys Lipids. 2021;235:105050. https://doi.org/10.1016/j.chemphyslip.2021.105050.Li W., Li Y., Chu Y., Wu W., Yu Q., Zhu X., Wang Q. PLCE1 promotes myocardial ischemia-reperfusion injury in H/R H9c2 cells and I/R rats by promoting inflammation. Biosci Rep. 2019;39(7):BSR20181613. https://doi.org/10.1042/BSR20181613.Li W., Li Y., Chu Y., Wu W., Yu Q., Zhu X., Wang Q. PLCE1 promotes myocardial ischemia-reperfusion injury in H/R H9c2 cells and I/R rats by promoting inflammation. Biosci Rep. 2019;39(7):BSR20181613. https://doi.org/10.1042/BSR20181613.Маздорова Е.В., Максимов В.Н., Орлов П.С., Шахматов С.Г., Рябиков А.Н., Воевода М.И., Малютина С.К. Анализ ассоциаций артериальной гипертензии с 16 генетическими маркерами, отобранными по данным полногеномных исследований. Артериальная гипертензия. 2022;28(1):46–57. https://doi.org/10.18705/1607-419X-2022-28-1-46-57.Mazdorova E.V., Maksimov V.N., Orlov P.S., Shakhmatov S.G., Ryabikov A.N., Voevoda M.I., Malyutina S.K. Analysis of associations of hypertension with 16 genetic markers selected according to genome-wide studies. Arterial Hypertension (Russian Federation). 2022;28(1):46–57. (In Russ.) https://doi.org/10.18705/1607-419X-2022-28-1-46-57.Yu S., Choi W.I., Choi Y.J., Kim H.Y., Hildebrandt F., Gee H.Y. PLCE1 regulates the migration, proliferation, and differentiation of podocytes. Exp Mol Med. 2020;52(4):594–603. https://doi.org/10.1038/s12276-020-0410-4.Yu S., Choi W.I., Choi Y.J., Kim H.Y., Hildebrandt F., Gee H.Y. PLCE1 regulates the migration, proliferation, and differentiation of podocytes. Exp Mol Med. 2020;52(4):594–603. https://doi.org/10.1038/s12276-020-0410-4.AbuMaziad A.S., Abusaleh R., Bhati S. Congenital nephrotic syndrome. J Perinatol. 2021;41(12):2704–2712. https://doi.org/10.1038/s41372-021-01279-0.AbuMaziad A.S., Abusaleh R., Bhati S. Congenital nephrotic syndrome. J Perinatol. 2021;41(12):2704–2712. https://doi.org/10.1038/s41372-021-01279-0.Atchison D.K., O’Connor C.L., Menon R., Otto E.A., Ganesh S.K., Wiggins R.C. et al. Hypertension induces glomerulosclerosis in phospholipase C-ε1 deficiency. Am J Physiol Renal Physiol. 2020;318(5):F1177–F1187. https://doi.org/10.1152/ajprenal.00541.2019.Atchison D.K., O’Connor C.L., Menon R., Otto E.A., Ganesh S.K., Wiggins R.C. et al. Hypertension induces glomerulosclerosis in phospholipase C-ε1 deficiency. Am J Physiol Renal Physiol. 2020;318(5):F1177–F1187. https://doi.org/10.1152/ajprenal.00541.2019.Головченко О.В., Абрамова М.Ю., Пономаренко И.В., Чурносов М.И. Локус rs833061 гена VEGF у беременных с преэклампсией ассоциирован с весом новорожденного. Генетика. 2021;57(9):1082–1088. https://doi.org/10.31857/S0016675821090034.Golovchenko O.V., Abramova M.Y., Ponomarenko I.V., Churnosov M.I. Locus rs833061 of the VEGF Gene in Pregnant Women with Preeclampsia Is Associated with Newborn Weight. Russ J Genet. 2021;57(9):1100–1105. https://doi.org/10.1134/S1022795421090039.

The authors declare that there are no conflicts of interest present.