{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:52:14Z","timestamp":1753890734160,"version":"3.41.2"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,7]],"date-time":"2022-11-07T00:00:00Z","timestamp":1667779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012434","name":"Middle-aged and Young Teachers' Basic Ability Promotion Project of Guangxi","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012434","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>The aim of this study was to investigate the relationship between potential functional single-nucleotide polymorphisms (SNPs) of the angiotensin-converting enzyme 2 (<jats:italic>ACE2<\/jats:italic>) gene and the pathogenesis of pre-eclampsia (PE) in Guangxi, China.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>A case\u2013control study was conducted involving 327 PE cases and 591 age-matched, normal, singleton pregnant women. Potential functional <jats:italic>ACE2<\/jats:italic> gene variants (rs2106809 A&amp;gt;G, rs6632677 G&amp;gt;C, and rs2074192 C&amp;gt;T) were selected and genotyped using kompetitive allele-specific PCR. The strength of the associations between the studied genetic variants and the risk of PE were evaluated using odds ratios (ORs) and corresponding 95% confidence intervals (CIs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Result<\/jats:title><jats:p>After adjusting for age and body mass index (BMI), unconditional logistic regression analysis showed that rs2106809 A&amp;gt;G was significantly associated with PE risk (AG <jats:italic>vs<\/jats:italic>. AA, OR = 1.43, 95% CI = 1.03\u20131.99, <jats:italic>p<\/jats:italic> = 0.034; AG\/GG <jats:italic>vs<\/jats:italic>. AA, OR = 1.45, 95% CI = 1.06\u20131.99, <jats:italic>p<\/jats:italic> = 0.019), especially with severe PE (AG <jats:italic>vs<\/jats:italic>. AA, adjusted OR = 1.70, 95% CI = 1.10\u20132.61; AG\/GG <jats:italic>vs<\/jats:italic>. AA, adjusted OR = 1.71, 95% CI = 1.14\u20132.57). Further stratified analysis showed that rs2106809 was even more pronounced in subjects in the pre-pregnancy BMI (pre-BMI) &amp;gt;23 kg\/m<jats:sup>2<\/jats:sup> (adjusted OR = 2.14, 95% CI = 1.32\u20133.45) and triglyceride (TG) &amp;gt;2.84 mmol\/L subgroups (adjusted OR = 1.81, 95% CI = 1.09\u20133.01) under the dominant genetic model. We also found that rs2106809 interacted with pre-BMI (<jats:italic>p<\/jats:italic><jats:sub>interaction<\/jats:sub> = 0.040), thereby affecting an individual\u2019s genetic susceptibility to PE. Multiple dimension reduction analysis demonstrated that rs2106809 made the best one-locus model, and the three-locus model was the best interaction model for predicting PE risk. Functional analysis suggested that rs2106809 A&amp;gt;G causes a change in the reliability of classifications of two putative splice sites in the <jats:italic>ACE2<\/jats:italic> gene, potentially regulating the expression of functional genes (<jats:italic>PIR<\/jats:italic>, <jats:italic>ACE2<\/jats:italic>, and <jats:italic>CLTRN<\/jats:italic>) in multiple tissues and cell lines (<jats:italic>p&amp;lt;<\/jats:italic> 0.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The <jats:italic>ACE2<\/jats:italic> gene rs2106809 A&amp;gt;G variant is significantly associated with the risk of PE <jats:italic>via<\/jats:italic> individual locus effects and\/or complex gene\u2013gene and gene\u2013environment interactions. Regulating the expression of functional genes such as <jats:italic>PIR<\/jats:italic>, <jats:italic>ACE2<\/jats:italic>, and <jats:italic>CLTRN<\/jats:italic> may be the molecular mechanism by which rs2106809 increases an individual\u2019s susceptibility to PE.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2022.926512","type":"journal-article","created":{"date-parts":[[2022,11,7]],"date-time":"2022-11-07T06:52:55Z","timestamp":1667803975000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Association and functional analysis of angiotensin-converting enzyme 2 genetic variants with the pathogenesis of pre-eclampsia"],"prefix":"10.3389","volume":"13","author":[{"given":"Gongchen","family":"Huang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linyuan","family":"Qin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangyuan","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0100180","article-title":"The 2011 survey on hypertensive disorders of pregnancy (HDP) in China: Prevalence, risk factors, complications, pregnancy and perinatal outcomes","volume":"9","author":"Ye","year":"2014","journal-title":"PloS One"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2014.00372","article-title":"Endothelial dysfunction and preeclampsia: role of oxidative stress","volume":"5","author":"S\u00e1nchez-Aranguren","year":"2014","journal-title":"Front Physiol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)17987-2","article-title":"Pre-eclampsia","volume":"365","author":"Sibai","year":"2005","journal-title":"Lancet (London England)"},{"key":"B4","article-title":"[Maternal complications and HELLP syndrome]","volume":"79","author":"V\u00e1zquez Rodr\u00edguez","year":"2011","journal-title":"Ginecol Y Obstetricia Mexico"},{"key":"B5","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1016\/j.bpobgyn.2011.01.006","article-title":"Epidemiology of pre-eclampsia and the other hypertensive disorders of pregnancy","volume":"25","author":"Hutcheon","year":"2011","journal-title":"Best Pract Res Clin Obstetr Gynaecol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"i1753","DOI":"10.1136\/bmj.i1753","article-title":"Clinical risk factors for pre-eclampsia determined in early pregnancy: systematic review and meta-analysis of large cohort studies","volume":"353","author":"Bartsch","year":"2016","journal-title":"BMJ (Clin Res Ed)"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.118.313276","article-title":"Preeclampsia: Pathophysiology, challenges, and perspectives","volume":"124","author":"Rana","year":"2019","journal-title":"Circ Res"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1034\/j.1399-0004.2000.580402.x","article-title":"Single nucleotide polymorphisms and the future of genetic epidemiology","volume":"58","author":"Schork","year":"2000","journal-title":"Clin Genet"},{"key":"B9","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/978-1-60327-411-1_1","article-title":"SNPs: impact on gene function and phenotype","volume":"578","author":"Shastry","year":"2009","journal-title":"Methods Mol Biol (Clifton NJ)"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1080\/01443615.2020.1837757","article-title":"AGTA study of the association between angiotensinogen () gene polymorphism (M235T) and preeclampsia in Thai pregnant women","volume":"41","author":"Jansaka","year":"2021","journal-title":"J Obstetr Gynaecol: J Institute Obstetrics Gynaecol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"144894","DOI":"10.1016\/j.gene.2020.144894","article-title":"STOX1 gene Y153H polymorphism is associated with early-onset preeclampsia in Turkish population","volume":"754","author":"Pinarbasi","year":"2020","journal-title":"Gene"},{"key":"B12","doi-asserted-by":"publisher","first-page":"5976","DOI":"10.1038\/s41467-020-19733-6","article-title":"Genetic predisposition to hypertension is associated with preeclampsia in European and central Asian women","volume":"11","author":"Steinthorsdottir","year":"2020","journal-title":"Nat Commun"},{"key":"B13","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1080\/15513815.2019.1675110","article-title":"Association of IL-6 -176G\u2009>\u2009C polymorphism with susceptibility to preeclampsia: A systematic review and meta-analysis","volume":"39","author":"Veisian","year":"2020","journal-title":"Fetal Pediatr Pathol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.preghy.2022.01.011","article-title":"Renin-angiotensin system in normal pregnancy and in preeclampsia: A comprehensive review","volume":"28","author":"Leal","year":"2022","journal-title":"Pregnancy Hypertension"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.hipert.2020.02.003","article-title":"Role of the renin-angiotensin system in pregnancy and preeclampsia","volume":"37","author":"Martell Claros","year":"2020","journal-title":"Hipertension Y Riesgo Vascular"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.4067\/S0034-98872013000200014","article-title":"Hypertension in women","volume":"141","author":"Tagle","year":"2013","journal-title":"Rev Med Chile"},{"key":"B17","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.ejphar.2015.03.090","article-title":"The renin-angiotensin system and its involvement in vascular disease","volume":"763","author":"van Thiel","year":"2015","journal-title":"Eur J Pharmacol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M200581200","article-title":"Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase","volume":"277","author":"Vickers","year":"2002","journal-title":"J Biol Chem"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00211.2021","article-title":"ACE2: a key modulator of the renin-angiotensin system and pregnancy","volume":"321","author":"Tamanna","year":"2021","journal-title":"Am J Physiol Regulatory Integr Comp Physiol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.lfs.2019.03.059","article-title":"Hypertension and hypertensive left ventricular hypertrophy are associated with ACE2 genetic polymorphism","volume":"225","author":"Fan","year":"2019","journal-title":"Life Sci"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1089\/dna.2020.5804","article-title":"ACE2Allele frequency of intron variants and its association with blood pressure","volume":"39","author":"Lozano-Gonzalez","year":"2020","journal-title":"DNA Cell Biol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djh075","article-title":"Assessing the probability that a positive report is false: an approach for molecular epidemiology studies","volume":"96","author":"Wacholder","year":"2004","journal-title":"J Natl Cancer Institute"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btf869","article-title":"Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions","volume":"19","author":"Hahn","year":"2003","journal-title":"Bioinf (Oxford England)"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2005.07.015","article-title":"Characterization and prediction of alternative splice sites","volume":"366","author":"Wang","year":"2006","journal-title":"Gene"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky407","article-title":"GWAS4D: multidimensional analysis of context-specific regulatory variant for human complex diseases and traits","volume":"46","author":"Huang","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)60279-6","article-title":"Pre-eclampsia","volume":"376","author":"Steegers","year":"2010","journal-title":"Lancet (London England)"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0b013e31828a3e24","article-title":"Epidemiology of obstetric-related ICU admissions in Maryland: 1999-2008*","volume":"41","author":"Wanderer","year":"2013","journal-title":"Crit Care Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/aer192","article-title":"Saving mothers' lives: reviewing maternal deaths to make motherhood safer: 2006-8: A review","volume":"107","author":"McClure","year":"2011","journal-title":"Br J Anaesthesia"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3785\/j.issn.1008-9292.2015.05.04","article-title":"Risk factors of recurrent preeclampsia and its relation to maternal and offspring outcome","volume":"44","author":"Zhang","year":"2015","journal-title":"Zhejiang Da Xue Xue Bao Yi Xue Ban  J Zhejiang Univ Med Sci"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/gaaa030","article-title":"Potential influence of COVID-19\/ACE2 on the female reproductive system","volume":"26","author":"Jing","year":"2020","journal-title":"Mol Hum Reprod"},{"key":"B31","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/1477-7827-11-5","article-title":"Utero-placental expression of angiotensin-(1-7) and ACE2 in the pregnant guinea-pig","volume":"11","author":"Vald\u00e9s","year":"2013","journal-title":"Reprod Biol Endocrinol: RB&E"},{"key":"B32","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1016\/j.ejogrb.2020.08.007","article-title":"COVID-19 infection: ACE2, pregnancy anpd preeclampsia","volume":"253","author":"Todros","year":"2020","journal-title":"Eur J Obstetr Gynecol Reprod Biol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/01443615.2021.2012438","article-title":"Associations between the TNMD rs4828038 and ACE2 rs879922 polymorphisms and preeclampsia susceptibility: A case-control study","volume":"42","author":"Song","year":"2022","journal-title":"J Obstetr Gynaecol: J Institute Obstetrics Gynaecol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0169223","article-title":"Maternal pre-pregnancy obesity is associated with altered placental transcriptome","volume":"12","author":"Altm\u00e4e","year":"2017","journal-title":"PloS One"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0186115","article-title":"Alterations in the placental methylome with maternal obesity and evidence for metabolic regulation","volume":"12","author":"Mitsuya","year":"2017","journal-title":"PloS One"},{"key":"B36","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1186\/s12944-018-0890-6","article-title":"Association of ACE2 polymorphisms with susceptibility to essential hypertension and dyslipidemia in xinjiang, China","volume":"17","author":"Pan","year":"2018","journal-title":"Lipids Health Dis"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1111\/jcpt.12625","article-title":"Relationship between genetic variants of ACE2 gene and circulating levels of ACE2 and its metabolites","volume":"43","author":"Chen","year":"2018","journal-title":"J Clin Pharm Ther"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-017-1791-x","article-title":"Intron retention as a component of regulated gene expression programs","volume":"136","author":"Jacob","year":"2017","journal-title":"Hum Genet"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2017.06.016","article-title":"How introns enhance gene expression","volume":"91","author":"Shaul","year":"2017","journal-title":"Int J Biochem Cell Biol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000003876","article-title":"Association between circulating levels of ACE2-Ang-(1-7)-MAS axis and ACE2 gene polymorphisms in hypertensive patients","volume":"95","author":"Liu","year":"2016","journal-title":"Medicine"},{"key":"B41","doi-asserted-by":"publisher","first-page":"27466","DOI":"10.1038\/srep27466","article-title":"The SDF-1 rs1801157 polymorphism is associated with cancer risk: An update pooled analysis and FPRP test of 17,876 participants","volume":"6","author":"Tong","year":"2016","journal-title":"Sci Rep"},{"key":"B42","doi-asserted-by":"publisher","first-page":"101770","DOI":"10.1016\/j.jogoh.2020.101770","article-title":"Correlation of serum collectrin level and preeclampsia onset: A case control study","volume":"50","author":"Al-Bayati","year":"2021","journal-title":"J Gynecol Obstetr Hum Reprod"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.679106","article-title":"NF-kappaB and its regulators during pregnancy","volume":"12","author":"Gomez-Chavez","year":"2021","journal-title":"Front Immunol"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.926512\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,7]],"date-time":"2022-11-07T06:53:00Z","timestamp":1667803980000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.926512\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,7]]},"references-count":43,"alternative-id":["10.3389\/fendo.2022.926512"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2022.926512","relation":{},"ISSN":["1664-2392"],"issn-type":[{"type":"electronic","value":"1664-2392"}],"subject":[],"published":{"date-parts":[[2022,11,7]]},"article-number":"926512"}}