{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T10:59:33Z","timestamp":1785841173704,"version":"3.56.0"},"reference-count":40,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T00:00:00Z","timestamp":1733961600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Perinatology","award":["2020-1-27"],"award-info":[{"award-number":["2020-1-27"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>The persistence of qPCR positivity for SARS-CoV-2 in individuals who recovered from COVID-19 raised several questions regarding viral transmission, with a special interest in healthcare professionals who may pose a risk of transmitting SARS-CoV-2. This issue highlights the necessity for identifying the genetic risk factors associated with persistent SARS-CoV-2 infection. A promising target for achieving this goal is the angiotensin-converting enzyme 2 (ACE2) gene, which has been associated with clinical characteristics of COVID-19 infection, such as severity. The analysis of samples from the first wave of the COVID-19 pandemic represents the initial response of the immune human system against this new virus, without the effect of vaccination or the presence of multiple strains. The aim of this study was to analyze the association of genetic variants in ACE2 with persistent SARS-CoV-2 infection. We conducted a case\u2013control study, including 151 healthcare workers who tested positive for SARS-CoV-2 by qPCR during the first wave of the COVID-19 pandemic, and who were followed up until their results were negative. ACE2 was sequenced through Sanger sequencing. The sequence was compared against a reference sequence and variants identified. Four ACE2 variants were associated with persistent SARS-CoV-2 qPCR positivity. Three of the variants with an effect on the resulting protein were associated with increased risk of persistent SARS-CoV-2 qPCR positivity, NG_012575.2:g.35481 C&gt;T, NG_012575.2:g.35483 G&gt;T and NG_012575.2:g.35498 G&gt;T. On the other hand, the rs2285666 (NG_012575.2:g.14934 G&gt;A) was associated with a higher risk for persistent SARS-CoV-2 qPCR positivity in women and rs4646150 (NG_012575.2:g.25701 G&gt;A) in men. The NG_012575.2:g.35498 G&gt;T variant represents an amino acid change with a possibly harmful effect on ACE2 function. Our results suggest that ACE2 variants might be useful for identifying the population at higher risk for developing persistent SARS-CoV-2-positive qPCR results. This knowledge can be helpful for designing health policies for protecting healthcare professionals and, in consequence, users of health services.<\/jats:p>","DOI":"10.3390\/microorganisms12122560","type":"journal-article","created":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T04:52:49Z","timestamp":1733979169000},"page":"2560","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Association of Single-Nucleotide Variants in ACE2 with the Persistence of Positive qPCR Test for SARS-CoV-2 in Healthcare Professionals During the First Wave of the COVID-19 Pandemic"],"prefix":"10.3390","volume":"12","author":[{"given":"Karina","family":"Jim\u00e9nez-Gil","sequence":"first","affiliation":[{"name":"Reproductive and Perinatal Health Research Department, National Institute of Perinatology, Mexico City 11000, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge Alberto","family":"Cer\u00f3n-Albarr\u00e1n","sequence":"additional","affiliation":[{"name":"Reproductive and Perinatal Health Research Department, National Institute of Perinatology, Mexico City 11000, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1188-0843","authenticated-orcid":false,"given":"Melissa Daniella","family":"Gonzalez-Fernandez","sequence":"additional","affiliation":[{"name":"Reproductive and Perinatal Health Research Department, National Institute of Perinatology, Mexico City 11000, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5658-4661","authenticated-orcid":false,"given":"Rosalba","family":"Sevilla-Montoya","sequence":"additional","affiliation":[{"name":"Reproductive and Perinatal Health Research Department, National Institute of Perinatology, Mexico City 11000, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2506-8784","authenticated-orcid":false,"given":"Alberto","family":"Hidalgo-Bravo","sequence":"additional","affiliation":[{"name":"Genomics Medicine Department, National Institute of Rehabilitation, Mexico City 14610, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5405-0482","authenticated-orcid":false,"given":"Javier","family":"Angeles-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Specialized Laboratories Division, Mexican Social Security Institute, Mexico City 06700, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2049-7387","authenticated-orcid":false,"given":"Daniel","family":"Montes-Herrera","sequence":"additional","affiliation":[{"name":"Specialized Laboratories Division, Mexican Social Security Institute, Mexico City 06700, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7091-8840","authenticated-orcid":false,"given":"Oscar","family":"Villavicencio-Carrisoza","sequence":"additional","affiliation":[{"name":"Immunobiochemistry Department, National Institute of Perinatology, Mexico City 11000, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen Selene","family":"Garc\u00eda-Romero","sequence":"additional","affiliation":[{"name":"Infectology and Immunology Department, National Institute of Perinatology, Mexico City 11000, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Esteban","family":"Mu\u00f1oz-Medina","sequence":"additional","affiliation":[{"name":"Quality of Supplies and Specialized Laboratories Coordination, Mexican Social Security Institute, Mexico City 37320, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8737-8935","authenticated-orcid":false,"given":"Irma Eloisa","family":"Monroy-Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Reproductive and Perinatal Health Research Department, National Institute of Perinatology, Mexico City 11000, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,12]]},"reference":[{"key":"ref_1","unstructured":"(2024, November 23). Word Health Organization Coronavirus Disease (COVID-19) Pandemic. Available online: https:\/\/www.who.int\/emergencies\/diseases\/novel-coronavirus-2019\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1007\/s13337-020-00605-y","article-title":"Decoding the global outbreak of COVID-19: The nature is behind the scene","volume":"31","author":"Das","year":"2020","journal-title":"Virus Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.biochi.2020.04.008","article-title":"Renin-angiotensin system at the heart of COVID-19 pandemic","volume":"174","author":"Alifano","year":"2020","journal-title":"Biochimie"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1161\/HYPERTENSIONAHA.119.14071","article-title":"Ang II (Angiotensin II) Conversion to Angiotensin-(1-7) in the Circulation Is POP (Prolyloligopeptidase)-Dependent and ACE2 (An-giotensin-Converting Enzyme 2)-Independent","volume":"75","author":"Serfozo","year":"2020","journal-title":"Hypertension"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1007\/s12016-022-08921-5","article-title":"Risk and Protective Factors for COVID-19 Morbidity, Severity, and Mortality","volume":"64","author":"Zhang","year":"2023","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"85","DOI":"10.2337\/db15-0399","article-title":"ACE2 Deficiency Worsens Epicardial Adipose Tissue Inflammation and Cardiac Dysfunction in Response to Diet-Induced Obesity","volume":"65","author":"Patel","year":"2016","journal-title":"Diabetes"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Chen, F., Zhang, Y., Li, X., Li, W., Liu, X., and Xue, X. (2021). The Impact of ACE2 Polymorphisms on COVID-19 Disease: Susceptibility, Severity, and Therapy. Front. Cell Infect. Microbiol., 11.","DOI":"10.3389\/fcimb.2021.753721"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Suryamohan, K., Diwanji, D., Stawiski, E.W., Gupta, R., Miersch, S., Liu, J., Chen, C., Jiang, Y.P., Fellouse, F.A., and Sathirapongsasuti, J.F. (2021). Human ACE2 Receptor Polymorphisms and Altered Susceptibility to SARS-CoV-2. Commun. Biol., 4.","DOI":"10.1038\/s42003-021-02030-3"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/s41435-020-0107-7","article-title":"Genetic variability in the expression of the SARS-CoV-2 host cell entry factors across popu-lations","volume":"21","author":"Sawalha","year":"2020","journal-title":"Genes Immun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/s41421-020-0147-1","article-title":"Comparative genetic analysis of the novel coronavirus (2019-nCoV\/SARS-CoV-2) receptor ACE2 in different populations","volume":"6","author":"Cao","year":"2020","journal-title":"Cell Discov."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1007\/s11427-020-1661-4","article-title":"Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts in Nanjing, China","volume":"63","author":"Hu","year":"2020","journal-title":"Sci. China Life Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1056\/NEJMoa2008457","article-title":"Presymptomatic SARS-CoV-2 Infections and Transmission in a Skilled Nursing Facility","volume":"382","author":"Arons","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/s41586-020-2196-x","article-title":"Virological assessment of hospitalized patients with COVID-2019","volume":"581","author":"Corman","year":"2020","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1007\/s10096-020-03913-9","article-title":"Viral RNA load as determined by cell culture as a management tool for discharge of SARS-CoV-2 patients from infectious disease wards","volume":"39","author":"Andreani","year":"2020","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1016\/j.jiph.2020.05.019","article-title":"SARS, MERS and COVID-19 among healthcare workers: A narrative review","volume":"13","author":"Xiao","year":"2020","journal-title":"J. Infect. Public Health"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1093\/aje\/kwaa191","article-title":"COVID-19 in Health-Care Workers: A Living Systematic Review and Meta-Analysis of Prevalence, Risk Factors, Clinical Characteristics, and Outcomes","volume":"190","author":"Franco","year":"2021","journal-title":"Am. J. Epidemiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"48","DOI":"10.21037\/atm.2020.02.06","article-title":"Which lessons shall we learn from the 2019 novel coronavirus outbreak?","volume":"8","author":"Mattiuzzi","year":"2020","journal-title":"Ann. Transl. Med."},{"key":"ref_18","unstructured":"(2024, November 23). World Health Organization COVID-19 Epidemiological Update\u20146 November 2024. Available online: https:\/\/www.who.int\/publications\/m\/item\/covid-19-epidemiological-update-edition-173."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Rogel-Ayala, D.G., Mu\u00f1oz-Medina, J.E., Vicente-Ju\u00e1rez, V.D., Grether-Gonz\u00e1lez, P., Morales-Barquet, D.A., Mart\u00ednez-Garc\u00eda, A.J., Echaniz-Aviles, M.O.L., Sevilla-Montoya, R., Mart\u00ednez-Ju\u00e1rez, A., and Artega-V\u00e1zquez, J. (2023). Association of the EPAS1 rs7557402 Polymorphism with Hemodynamically Significant Patent Ductus Arteriosus Closure Failure in Premature Newborns under Pharmacological Treatment with Ibuprofen. Diagnostics, 13.","DOI":"10.3390\/diagnostics13152558"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.annepidem.2020.08.005","article-title":"Clinical characteristics and risk factors for mortality of patients with COVID-19 in a large data set from Mexico","volume":"52","year":"2020","journal-title":"Ann. Epidemiol."},{"key":"ref_21","unstructured":"(2024, November 23). Coronavirus COVID19 Weekly Technical Reports 2023. Available online: https:\/\/www.gob.mx\/salud\/documentos\/coronavirus-covid19-informe-tecnico-semanal."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"611.e9","DOI":"10.1016\/j.cmi.2021.11.002","article-title":"Female gender is associated with long COVID syndrome: A prospective cohort study","volume":"28","author":"Bai","year":"2022","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/S2213-2600(23)00414-9","article-title":"The effectiveness of COVID-19 vaccines to prevent long COVID symptoms: Staggered cohort study of data from the UK, Spain, and Estonia","volume":"12","author":"Kolde","year":"2024","journal-title":"Lancet Respir. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.1001\/jama.2023.8823","article-title":"Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection","volume":"329","author":"Thaweethai","year":"2023","journal-title":"JAMA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"104688","DOI":"10.1016\/j.idnow.2023.104688","article-title":"COVID-19 long-term sequelae: Omicron versus Alpha and Delta variants","volume":"53","year":"2023","journal-title":"Infect. Dis. Now"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"453","DOI":"10.7326\/M20-3337","article-title":"Dynamics and Correlation Among Viral Positivity, Seroconversion, and Disease Severity in COVID-19: A Retrospective Study","volume":"174","author":"Fu","year":"2021","journal-title":"Ann. Intern. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.tig.2014.04.006","article-title":"Exposing synonymous mutations","volume":"30","author":"Hunt","year":"2014","journal-title":"Trends Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1038\/nrg3051","article-title":"Understanding the contribution of synonymous mutations to human disease","volume":"12","author":"Sauna","year":"2011","journal-title":"Nat. Rev. Genet."},{"key":"ref_29","first-page":"2675","article-title":"The missing puzzle piece: Splicing mutations","volume":"6","author":"Lewandowska","year":"2013","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.medcli.2014.02.021","article-title":"Alternative splicing regulation: Implications in cancer diagnosis and treatment","volume":"144","year":"2015","journal-title":"Med. Clin."},{"key":"ref_31","unstructured":"Ensembl (2024, November 23). ACE2. Available online: http:\/\/www.ensembl.org\/index.html."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1093\/jmcb\/mjz033","article-title":"Aberrant alternative splicing in breast cancer","volume":"11","author":"Yang","year":"2019","journal-title":"J. Mol. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1136\/jmg.2004.029538","article-title":"Splicing in action: Assessing disease causing sequence changes","volume":"42","author":"Bralle","year":"2005","journal-title":"J. Med. Genet."},{"key":"ref_34","first-page":"1483","article-title":"Mechanism and regulation of the nonsense mediated decay pathway","volume":"44","author":"Hug","year":"2016","journal-title":"Investig. \u00c1cidos Nucleicos"},{"key":"ref_35","unstructured":"(2024, November 23). rs2285666 (SNP)\u2014Citations\u2014Homo_Sapiens\u2014Ensembl Genome Browser. Available online: https:\/\/www.ensembl.org\/Homo_sapiens\/Variation\/Citations?db=core;r=X:15591725-15592725;v=rs2285666;vdb=variation;vf=1109761140."},{"key":"ref_36","first-page":"9","article-title":"The Association of Angiotensin-Converting Enzyme 2 Polymorphism and SARS-CoV-2 Infection in the Iraqi Population","volume":"78","author":"Noaman","year":"2023","journal-title":"Arch. Razi Inst."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s12985-022-01782-6","article-title":"SNPs of ACE1 (rs4343) and ACE2 (rs2285666) genes are linked to SARS-CoV-2 infection but not with the severity of disease","volume":"19","author":"Alimoradi","year":"2022","journal-title":"Virol. J."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Angulo-Aguado, M., Corredor-Orlandelli, D., Carrillo-Mart\u00ednez, J.C., Gonzalez-Cornejo, M., Pineda-Mateus, E., Rojas, C., Tria-na-Fonseca, P., Contreras Bravo, N.C., Morel, A., and Parra Abaunza, K. (2022). Association Between the LZTFL1 rs11385942 Polymorphism and COVID-19 Severity in Colombian Population. Front. Med., 9.","DOI":"10.3389\/fmed.2022.910098"},{"key":"ref_39","unstructured":"(2024, November 23). Phylodynamics of Pandemic Coronavirus in Mexico. Available online: https:\/\/gisaid.org\/phylodynamics\/mexico\/."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e29708","DOI":"10.1002\/jmv.29708","article-title":"Persistence of SARS-CoV-2 infection and viral intra- and inter-host evolution in COVID-19 hospitalized patients","volume":"96","author":"Pavia","year":"2024","journal-title":"J. Med. Virol."}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/12\/12\/2560\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:53:19Z","timestamp":1760115199000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/12\/12\/2560"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,12]]},"references-count":40,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["microorganisms12122560"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms12122560","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,12]]}}}