{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T12:01:31Z","timestamp":1775908891824,"version":"3.50.1"},"reference-count":75,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,8,27]],"date-time":"2021-08-27T00:00:00Z","timestamp":1630022400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>\n                    Angiotensin-converting enzyme-2 (\n                    <jats:italic>ACE2<\/jats:italic>\n                    ) receptor has been identified as the key adhesion molecule for the transmission of the SARS-CoV-2. However, there is no evidence that human genetic variation in ACE2 is singularly responsible for COVID-19 susceptibility. Therefore, we performed an integrative multi-level characterization of genes that interact with ACE2 (ACE2-gene network) for their statistically enriched biological properties in the context of COVID-19. The phenome-wide association of 51 genes including ACE2 with 4,756 traits categorized into 26 phenotype categories, showed enrichment of immunological, respiratory, environmental, skeletal, dermatological, and metabolic domains (\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 4e-4). Transcriptomic regulation of ACE2-gene network was enriched for tissue-specificity in kidney, small intestine, and colon (\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 4.7e-4). Leveraging the drug-gene interaction database we identified 47 drugs, including dexamethasone and spironolactone, among others. Considering genetic variants within \u00b1 10 kb of ACE2-network genes we identified miRNAs whose binding sites may be altered as a consequence of genetic variation. The identified miRNAs revealed statistical over-representation of inflammation, aging, diabetes, and heart conditions. The genetic variant associations in\n                    <jats:italic>RORA<\/jats:italic>\n                    ,\n                    <jats:italic>SLC12A6<\/jats:italic>\n                    , and\n                    <jats:italic>SLC6A19<\/jats:italic>\n                    genes were observed in genome-wide association study (GWAS) of COVID-19 susceptibility. We also report the GWAS-identified variant in 3p21.31 locus, serves as trans-QTL for\n                    <jats:italic>RORA<\/jats:italic>\n                    and\n                    <jats:italic>RORC<\/jats:italic>\n                    genes. Overall, functional characterization of ACE2-gene network highlights several potential mechanisms in COVID-19 susceptibility. The data can also be accessed at\n                    <jats:ext-link>https:\/\/gpwhiz.github.io\/ACE2Netlas\/<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.3389\/fgene.2021.698033","type":"journal-article","created":{"date-parts":[[2021,9,6]],"date-time":"2021-09-06T11:25:19Z","timestamp":1630927519000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["ACE2 Netlas: In silico Functional Characterization and Drug-Gene Interactions of ACE2 Gene Network to Understand Its Potential Involvement in COVID-19 Susceptibility"],"prefix":"10.3389","volume":"12","author":[{"given":"Gita A.","family":"Pathak","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank R.","family":"Wendt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aranyak","family":"Goswami","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dora","family":"Koller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Flavio","family":"De Angelis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"COVID-19 Host Genetics Initiative","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renato","family":"Polimanti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,8,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1101\/787903","article-title":"The GTEx Consortium atlas of genetic regulatory effects across human tissues.","author":"Aguet","year":"2019","journal-title":"bioRxiv"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.2215\/CJN.09730620","article-title":"COVID-19 in Patients with Kidney Disease.","volume":"15","author":"Ajaimy","year":"2020","journal-title":"Clin. 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