{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:32:36Z","timestamp":1760146356803,"version":"build-2065373602"},"reference-count":37,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T00:00:00Z","timestamp":1730246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012632","name":"Nazarbayev University","doi-asserted-by":"publisher","award":["021220CRP0822"],"award-info":[{"award-number":["021220CRP0822"]}],"id":[{"id":"10.13039\/501100012632","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>SARS-CoV-2 utilizes the angiotensin-converting enzyme 2 (ACE2) receptors located on membranes to enter host cells. Nevertheless, the ACE2 gene primarily encodes for a zinc metalloproteinase, which is a part of the renin\u2013angiotensin system (RAS). ACE2 downregulation results in the deregulation of RAS in favor of pro-fibrosis, pro-apoptosis, oxidative stress, pro-inflammation, aldosterone production and release, and blood vessel contraction axis. ACE2 is highly expressed in the placenta. There are both axes of the RAS system in the placenta. This study aims to assess the perinatal outcomes with ACE2 receptor polymorphisms in pregnant women infected with SARS-CoV-2 during pregnancy. The case-control study was conducted to determine the association of ACE2 single-nucleotide polymorphisms in 171 COVID-19-positive pregnant subjects and 112 control subjects. The recessive mutations of rs2158082 and rs4830974 were associated with an increased risk of low birthweight and preterm birth, whereas the dominant mutation of rs2285666 (CT + TT) was associated with decreased odds of low birthweight. COVID-19 was not a significant factor contributing to the adverse perinatal outcomes in our sampling. These findings may help to clarify the controversy regarding the increased risk of adverse perinatal outcomes observed during COVID-19 as well as provide new perspectives for research on the genetic factors associated with a higher risk of adverse perinatal outcomes.<\/jats:p>","DOI":"10.3390\/v16111696","type":"journal-article","created":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T09:10:44Z","timestamp":1730279444000},"page":"1696","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Association of ACE2 Gene Variants with Adverse Perinatal Outcomes in COVID-19 Infected Pregnant Women in Kazakhstan"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0498-2876","authenticated-orcid":false,"given":"Kymbat","family":"Mukhtarova","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Astana 010000, Kazakhstan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5892-1860","authenticated-orcid":false,"given":"Karina","family":"Tazhibayeva","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology #1, NJSC \u201cAstana Medical University\u201d, Astana 010000, Kazakhstan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8701-2471","authenticated-orcid":false,"given":"Aigul","family":"Myrzabekova","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology #1, NJSC \u201cAstana Medical University\u201d, Astana 010000, Kazakhstan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7668-5614","authenticated-orcid":false,"given":"Vitaliy","family":"Koikov","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology #1, NJSC \u201cAstana Medical University\u201d, Astana 010000, Kazakhstan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zaituna","family":"Khamidullina","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology #1, NJSC \u201cAstana Medical University\u201d, Astana 010000, Kazakhstan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3914-5154","authenticated-orcid":false,"given":"Milan","family":"Terzic","sequence":"additional","affiliation":[{"name":"Department of Surgery, School of Medicine, Nazarbayev University, Astana 010000, Kazakhstan"},{"name":"Clinical Academic Department of Women\u2019s Health, CF \u201cUniversity Medical Center\u201d, Astana 010000, Kazakhstan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gauri","family":"Bapayeva","sequence":"additional","affiliation":[{"name":"Clinical Academic Department of Women\u2019s Health, CF \u201cUniversity Medical Center\u201d, Astana 010000, Kazakhstan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saule","family":"Zhumambayeva","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology #1, NJSC \u201cAstana Medical University\u201d, Astana 010000, Kazakhstan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1755-0490","authenticated-orcid":false,"given":"Azliyati","family":"Azizan","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine, Touro University, Henderson, NV 89014, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5734-7468","authenticated-orcid":false,"given":"Antonio","family":"Sarr\u00eda-Santamera","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Astana 010000, Kazakhstan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,30]]},"reference":[{"key":"ref_1","first-page":"174","article-title":"SARS-CoV-2, SARS-CoV, and MERS-COV: A comparative overview","volume":"28","author":"Rabaan","year":"2020","journal-title":"Infez. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"110231","DOI":"10.1016\/j.mehy.2020.110231","article-title":"COVID-19 and the renin-angiotensin system (RAS): A spark that sets the forest alight?","volume":"144","author":"Wiese","year":"2020","journal-title":"Med. Hypotheses"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"145102","DOI":"10.1016\/j.gene.2020.145102","article-title":"Angiotensin-converting enzymes (ACE, ACE2) gene variants and COVID-19 outcome","volume":"762","author":"Albaiceta","year":"2020","journal-title":"Gene"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Badran, E.F., Darwish, R.M., Khader, Y., AlMasri, R., Al Jaberi, M., AlMasri, M., AlSa\u2019di, F., Yosef, L.A., and Al-Badaineh, N. (2021). Adverse pregnancy outcomes during the COVID-19 lockdown. A descriptive study. BMC Pregnancy Childbirth, 21.","DOI":"10.1186\/s12884-021-04221-6"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.ajog.2020.02.017","article-title":"Coronavirus Disease 2019 (COVID-19) and pregnancy: What obstetricians need to know","volume":"222","author":"Rasmussen","year":"2020","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.1042\/CS20210284","article-title":"Role of ACE2 in pregnancy and potential implications for COVID-19 susceptibility","volume":"135","author":"Stoll","year":"2021","journal-title":"Clin. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.placenta.2020.07.022","article-title":"Placental barrier against COVID-19","volume":"99","author":"Takada","year":"2020","journal-title":"Placenta"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e13306","DOI":"10.1111\/aji.13306","article-title":"COVID-19 in pregnancy: Placental and neonatal involvement","volume":"84","author":"Prochaska","year":"2020","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"100145","DOI":"10.1016\/j.ajogmf.2020.100145","article-title":"Vertical transmission of coronavirus disease 2019: Severe acute respiratory syndrome coronavirus 2 RNA on the fetal side of the placenta in pregnancies with coronavirus disease 2019-positive mothers and neonates at birth","volume":"2","author":"Morotti","year":"2020","journal-title":"Am. J. Obstet. Gynecol. MFM"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"m3320","DOI":"10.1136\/bmj.m3320","article-title":"Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: Living systematic review and meta-analysis","volume":"370","author":"Allotey","year":"2020","journal-title":"BMJ"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"E540","DOI":"10.1503\/cmaj.202604","article-title":"The impact of COVID-19 on pregnancy outcomes: A systematic review and meta-analysis","volume":"193","author":"Wei","year":"2021","journal-title":"CMAJ Can. Med. Assoc. J."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Pathirathna, M.L., Samarasekara, B.P.P., Dasanayake, T.S., Saravanakumar, P., and Weerasekara, I. (2022). Adverse Perinatal Outcomes in COVID-19 Infected Pregnant Women: A Systematic Review and Meta-Analysis. Healthcare, 10.","DOI":"10.3390\/healthcare10020203"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"100258","DOI":"10.1016\/j.ajogmf.2020.100258","article-title":"Decreased incidence of preterm birth during coronavirus disease 2019 pandemic","volume":"2","author":"Berghella","year":"2020","journal-title":"Am. J. Obstet. Gynecol. MFM"},{"key":"ref_14","unstructured":"Spanish Obstetric Emergency, Group, and P\u00e9rez, O.M. (2020). The association between COVID-19 and preterm delivery: A cohort study with a multivariate analysis. medRxiv."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1159\/000509290","article-title":"COVID-19 (SARS-CoV-2) Infection in Pregnancy: A Systematic Review","volume":"85","author":"Akhtar","year":"2020","journal-title":"Gynecol. Obstet. Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1928","DOI":"10.1093\/bioinformatics\/btl268","article-title":"SNPStats: A web tool for the analysis of association studies","volume":"22","author":"Valls","year":"2006","journal-title":"Bioinformatics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e003075","DOI":"10.1136\/bmjgh-2020-003075","article-title":"Unprecedented reduction in births of very low birthweight (VLBW) and extremely low birthweight (ELBW) infants during the COVID-19 lockdown in Ireland: A \u2018natural experiment\u2019 allowing analysis of data from the prior two decades","volume":"5","author":"Philip","year":"2020","journal-title":"BMJ Glob. Health"},{"key":"ref_18","first-page":"100049","article-title":"Socioeconomic inequalities in low birth weight risk before and during the COVID-19 pandemic in Argentina: A cross-sectional study","volume":"2","author":"Cuestas","year":"2021","journal-title":"Lancet Reg. Health"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e759","DOI":"10.1016\/S2214-109X(21)00079-6","article-title":"Effects of the COVID-19 pandemic on maternal and perinatal outcomes: A systematic review and meta-analysis","volume":"9","author":"Chmielewska","year":"2021","journal-title":"Lancet Glob. Health"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Kuandyk (Sabitova), A., Ortega, M.-A., Ntegwa, M.J., and Sarria-Santamera, A. (2024). Impact of the COVID-19 pandemic on access to and delivery of maternal and child healthcare services in low-and middle-income countries: A systematic review of the literature. Front. Public Health, 12.","DOI":"10.3389\/fpubh.2024.1346268"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1111\/iji.12598","article-title":"Angiotensin-converting enzyme 2 rs2285666 polymorphism and clinical parameters as the determinants of COVID-19 severity in Iranian population","volume":"49","author":"Khalilzadeh","year":"2022","journal-title":"Int. J. Immunogenet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.omtm.2020.06.017","article-title":"The Two Faces of ACE2: The Role of ACE2 Receptor and Its Polymorphisms in Hypertension and COVID-19","volume":"18","author":"Bosso","year":"2020","journal-title":"Mol. Therapy. Methods Clin. Dev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s40246-023-00501-8","article-title":"The impact of ACE2 polymorphisms (rs1978124, rs2285666, and rs2074192) and ACE1 rs1799752 in the mortality rate of COVID-19 in different SARS-CoV-2 variants","volume":"17","author":"Sheikhian","year":"2023","journal-title":"Hum. Genom."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Tamanna, S., Clifton, V.L., Rae, K., van Helden, D.F., Lumbers, E.R., and Pringle, K.G. (2020). Angiotensin Converting Enzyme 2 (ACE2) in Pregnancy: Preeclampsia and Small for Gestational Age. Front. Physiol., 11.","DOI":"10.3389\/fphys.2020.590787"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1596","DOI":"10.1159\/000494449","article-title":"Fetal But Not Maternal Angiotensin Converting Enzyme (ACE)-2 Gene Rs2074192 Polymorphism is Associated with Increased Risk of Being a Small For Gestational Age (SGA) Newborn","volume":"43","author":"He","year":"2018","journal-title":"Kidney Blood Press. Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Lye, P., Dunk, C.E., Zhang, J., Wei, Y., Nakpu, J., Hamada, H., Imperio, G.E., Bloise, E., Matthews, S.G., and Lye, S.J. (2021). ACE2 Is Expressed in Immune Cells That Infiltrate the Placenta in Infection-Associated Preterm Birth. Cells, 10.","DOI":"10.3390\/cells10071724"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.placenta.2021.01.008","article-title":"Increased placental expression of angiotensin-converting enzyme 2, the receptor of SARS-CoV-2, associated with hypoxia in twin anemia-polycythemia sequence (TAPS)","volume":"105","author":"Mao","year":"2021","journal-title":"Placenta"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Hamilton, S., Oomomian, Y., Stephen, G., Shynlova, O., Tower, C.L., Garrod, A., Lye, S.J., and Jones, R.L. (2012). Macrophages Infiltrate the Human and Rat Decidua During Term and Preterm Labor: Evidence That Decidual Inflammation Precedes Labor1. Biol. Reprod., 86.","DOI":"10.1095\/biolreprod.111.095505"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e95","DOI":"10.1016\/S2589-7500(21)00250-8","article-title":"The effect of maternal SARS-CoV-2 infection timing on birth outcomes: A retrospective multicentre cohort study","volume":"4","author":"Piekos","year":"2022","journal-title":"Lancet Digit. Health"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1080\/00313020600696280","article-title":"The placentas of patients with severe acute respiratory syndrome: A pathophysiological evaluation","volume":"38","author":"Ng","year":"2006","journal-title":"Pathology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1093\/ajcp\/aqaa089","article-title":"Placental Pathology in COVID-19","volume":"154","author":"Shanes","year":"2020","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Wong, Y.P., Khong, T.Y., and Tan, G.C. (2021). The Effects of COVID-19 on Placenta and Pregnancy: What Do We Know So Far?. Diagnostics, 11.","DOI":"10.3390\/diagnostics11010094"},{"key":"ref_33","first-page":"418","article-title":"Pregnancy with new coronavirus infection: Clinical characteristics and placental pathological analysis of three cases","volume":"49","author":"Chen","year":"2020","journal-title":"Chin. J. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.placenta.2021.12.013","article-title":"Massive perivillous fibrin deposition of the placenta and pregnancy outcome: A retrospective observational study","volume":"117","author":"Lampi","year":"2022","journal-title":"Placenta"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"S147","DOI":"10.1093\/ajcp\/aqab191.313","article-title":"Massive Perivillous Fibrin Deposition-A Cause of Recurrent Fetal Demise: A Case Report","volume":"156","author":"Pandiri","year":"2021","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.placenta.2020.08.015","article-title":"Consistent localization of SARS-CoV-2 spike glycoprotein and ACE2 over TMPRSS2 predominance in placental villi of 15 COVID-19 positive maternal-fetal dyads","volume":"100","author":"Taglauer","year":"2020","journal-title":"Placenta"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.jinf.2024.01.001","article-title":"Stillbirths due to placental COVID infection associated with chronic histiocytic intervillositis do not recur in subsequent pregnancies","volume":"88","author":"Cornish","year":"2024","journal-title":"J. Infect."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/16\/11\/1696\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:23:54Z","timestamp":1760113434000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/16\/11\/1696"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,30]]},"references-count":37,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["v16111696"],"URL":"https:\/\/doi.org\/10.3390\/v16111696","relation":{},"ISSN":["1999-4915"],"issn-type":[{"type":"electronic","value":"1999-4915"}],"subject":[],"published":{"date-parts":[[2024,10,30]]}}}