Dataset Information

Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium.

ABSTRACT:

Background

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.

SUBMITTER: Kasela S

PROVIDER: S-EPMC8059115 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium.

Kasela Silva S Ortega Victor E VE Martorella Molly M Garudadri Suresh S Nguyen Jenna J Ampleford Elizabeth E Pasanen Anu A Nerella Srilaxmi S Buschur Kristina L KL Barjaktarevic Igor Z IZ Barr R Graham RG Bleecker Eugene R ER Bowler Russell P RP Comellas Alejandro P AP Cooper Christopher B CB Couper David J DJ Criner Gerard J GJ Curtis Jeffrey L JL Han MeiLan K MK Hansel Nadia N NN Hoffman Eric A EA Kaner Robert J RJ Krishnan Jerry A JA Martinez Fernando J FJ McDonald Merry-Lynn N MN Meyers Deborah A DA Paine Robert R Peters Stephen P SP Castro Mario M Denlinger Loren C LC Erzurum Serpil C SC Fahy John V JV Israel Elliot E Jarjour Nizar N NN Levy Bruce D BD Li Xingnan X Moore Wendy C WC Wenzel Sally E SE Zein Joe J Langelier Charles C Woodruff Prescott G PG Lappalainen Tuuli T Christenson Stephanie A SA

Genome medicine 20210421 1

<h4>Background</h4>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 COV ...[more]

PMID: 33883027

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Project description:Upregulation of Expression of the Ubiquitin Carboxyl Terminal Hydrolase L1 Gene in Human Airway Epithelium of Cigarette Smokers; The microarray data deposited here is from 11 HG-U133A GeneChips, from 5 normal non-smokers and 6 phenotypic normal smokers, large airways. Samples from the small airways of these individuals have been obtained and analyzed using the HG-U133A GeneChip; the small airway samples are in GEO Accession Number GSE 3320, and the data analysis is described in Harvey, B-G; Heguy, A.; Leopold, P.L.; Carolan, B.; Ferris, B. and Crystal R.G. Modification of Gene Expression of the Small Airway Epithelium in Response to Cigarette Smoking. J. Mol. Med (in press). These data are part of a study aimed at understanding how cigarette smoking modifies neuroendocrine cells, in which microarray analysis with TaqMan confirmation was used to assess airway epithelial samples obtained by fiberoptic bronchoscopy from 81 individuals (normal nonsmokers, normal smokers, smokers with early COPD and smokers with established COPD). Of 11 genes considered to be neuroendocrine cell-specific, only ubiquitin C-terminal hydrolase L1(UCHL1), a member of the ubiquitin proteasome pathway, was consistently upregulated in smokers compared to nonsmokers. Up-regulation of UCHL1 at the protein level was observed with immunohistochemistry of bronchial biopsies of smokers compared to nonsmokers. Interestingly, however, while UCHL1 expression was present only in neuroendocrine cells of the airway epithelium in nonsmokers, UCHL1 expression was also expressed in ciliated epithelial cells in smokers, an intriguing observation in light of recent observations that ciliated cells can are capable of transdifferentiating to other airway epithelium. In the context that UCHL1 is involved in the degradation of unwanted, misfolded or damaged proteins within the cell and is overexpressed in >50% of lung cancers, its overexpression in chronic smokers may represent an early event in the complex transformation from normal epithelium to overt malignancy. Experiment Overall Design: comparison of gene expression in airway epithelial cells of the large airways of phenotypic normal smokers vs normal non-smokers

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Dataset Information

Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium.

Background

Methods

Results

Conclusions

Publications

Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium.

Similar Datasets

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