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<jats:title>Background<\/jats:title>\n                    <jats:p>The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related\n                      <jats:italic>ACE2<\/jats:italic>\n                      gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond\n                      <jats:italic>ACE2<\/jats:italic>\n                      binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We found that\n                      <jats:italic>ACE2<\/jats:italic>\n                      expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding\n                      <jats:italic>ACE2<\/jats:italic>\n                      isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13073-021-00866-2","type":"journal-article","created":{"date-parts":[[2021,4,21]],"date-time":"2021-04-21T09:06:25Z","timestamp":1618995985000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium"],"prefix":"10.1186","volume":"13","author":[{"name":"NHLBI SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS)","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4362-0034","authenticated-orcid":false,"given":"Silva","family":"Kasela","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victor E.","family":"Ortega","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Molly","family":"Martorella","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suresh","family":"Garudadri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jenna","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Ampleford","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anu","family":"Pasanen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Srilaxmi","family":"Nerella","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristina L.","family":"Buschur","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igor Z.","family":"Barjaktarevic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R. 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Github. https:\/\/github.com\/LappalainenLab\/spiromics-covid19-eqtl (2020)."}],"container-title":["Genome Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13073-021-00866-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13073-021-00866-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13073-021-00866-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,21]],"date-time":"2021-04-21T09:40:23Z","timestamp":1618998023000},"score":1,"resource":{"primary":{"URL":"https:\/\/genomemedicine.biomedcentral.com\/articles\/10.1186\/s13073-021-00866-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,21]]},"references-count":82,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["866"],"URL":"https:\/\/doi.org\/10.1186\/s13073-021-00866-2","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.10.01.20202820","asserted-by":"object"}]},"ISSN":["1756-994X"],"issn-type":[{"value":"1756-994X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,21]]},"assertion":[{"value":"10 November 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 March 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 April 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The SPIROMICS study was approved by the Institutional Review Boards at each cooperating institutions: Columbia University IRB 2 (AAAE9315), University of Iowa IRB-01 (201308719), Johns Hopkins IRB-5 (NA_00035701), UCLA Medical IRB 1 (MIRB1) (10001740\/18-000403), University of Michigan IRBMED B1 Board (HUM00036346\/ HUM00141222), National Jewish Health IRB (HS2678), UCSF IRB Parnassus Panel (10-03169), Temple University IRB A2 (21416), U of Alabama at Birmingham IRB #2 (120906004), University of Illinois IRB #3 (2013-0939), University of Utah IRB Panel Review Board 5 (00027298\/ 00108836), Wake Forest University IRB #5 (00012805\/00048727), UNC Non-Biomedical IRB (10-0048), UCLA Medical IRB 1 (MIRB1) (18-000458), and University of Iowa IRB-01 (201003733). All participants provided written informed consent. The SARP and MAST studies were approved by the appropriate institutional review board at the participating sites and all participants provided written informed consent. The research conformed to the principles of the Helsinki Declaration.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"S.A.C. advises for AstraZeneca, GlaxoSmithKline, Glenmark Pharmaceuticals, and Amgen, gave invited lectures to Sonovion and Genentech, and writes for UpToDate. T.L. advises and has equity in Variant Bio and is a member of the scientific advisory board of Goldfinch Bio. V.E.O. has served and currently serves on Independent Data and Monitoring Committee for Regeneron and Sanofi for COVID-19 therapeutic clinical trials unrelated to the current manuscript. The remaining authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"66"}}