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dc.creatorKasela, Silva
dc.creatorOrtega, Victor E.
dc.creatorChristenson, Stephanie A.
dc.creatorMartorella, Molly
dc.creatorGarudadri, Suresh
dc.creatorNguyen, Jenna
dc.creatorAmpleford, Elizabeth
dc.creatorPasanen, Anu
dc.creatorNerella, Srilaxmi
dc.creatorBuschur, Kristina L.
dc.creatorBarjaktarevic, Igor Z.
dc.creatorBarr, R. Graham
dc.creatorBleecker, Eugene R.
dc.creatorBowler, Russell P.
dc.creatorComellas, Alejandro P.
dc.creatorCooper, Christopher B.
dc.creatorCouper, David J.
dc.creatorCriner, Gerard J.
dc.creatorCurtis, Jeffrey L.
dc.creatorHan, MeiLan K.
dc.creatorHansel, Nadia N.
dc.creatorHoffman, Eric A.
dc.creatorKaner, Robert J.
dc.creatorKrishnan, Jerry A.
dc.creatorMartinez, Fernando J.
dc.creatorMcDonald, Merry-Lynn N.
dc.creatorMeyers, Deborah A.
dc.creatorPaine, Robert
dc.creatorPeter, Stephen P.
dc.creatorCastro, Mario
dc.creatorDenlinger, Loren C.
dc.creatorErzurum, Serpil C.
dc.creatorFahy, John V.
dc.creatorIsrael, Elliot
dc.creatorJarjour, Nizar N.
dc.creatorLevy, Bruce D.
dc.creatorLi, Xingnan
dc.creatorMoore, Wendy C.
dc.creatorWenzel, Sally E.
dc.creatorZein, Joe
dc.creatorLangelier, Charles
dc.creatorWoodruff, Prescott G.
dc.creatorLappalainen, Tuuli
dc.date.accessioned2021-10-26T21:17:41Z
dc.date.available2021-10-26T21:17:41Z
dc.date.issued2021-04-21
dc.identifier.citationKasela, S., Ortega, V.E., Martorella, M. et al. Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium. Genome Med 13, 66 (2021). https://doi.org/10.1186/s13073-021-00866-2
dc.identifier.issn1756-994X
dc.identifier.doihttp://dx.doi.org/10.34944/dspace/7005
dc.identifier.urihttp://hdl.handle.net/20.500.12613/7024
dc.description.abstractBackground: 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. Methods: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 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 ACE2 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. Results: We found that ACE2 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 ACE2 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. Conclusions: 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.
dc.format.extent17 pages
dc.languageEnglish
dc.language.isoeng
dc.relation.ispartofCOVID-19 Research
dc.relation.haspartGenome Medicine, Vol. 13, No. 66
dc.relation.isreferencedbyBMC
dc.rightsAttribution CC BY
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectCOVID-19
dc.subjectSARS-CoV-2
dc.subjectace2
dc.subjecteQTL
dc.subjectBronchial epithelium
dc.titleGenetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium
dc.typeText
dc.type.genreJournal article
dc.contributor.groupNHLBI SubPopulations and InteRmediate Outcome Measures In COPD Study(SPIROMICS)
dc.contributor.groupNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
dc.description.departmentThoracic Medicine and Surgery
dc.relation.doihttps://doi.org/10.1186/s13073-021-00866-2
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
dc.description.schoolcollegeLewis Katz School of Medicine
dc.temple.creatorCriner, Gerard J.
refterms.dateFOA2021-10-26T21:17:41Z


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