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

Publication ,  Journal Article
Kasela, S; Ortega, VE; Martorella, M; Garudadri, S; Nguyen, J; Ampleford, E; Pasanen, A; Nerella, S; Buschur, KL; Barjaktarevic, IZ; Barr, RG ...
Published in: Genome Med
April 21, 2021

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.

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Published In

Genome Med

DOI

EISSN

1756-994X

Publication Date

April 21, 2021

Volume

13

Issue

1

Start / End Page

66

Location

England

Related Subject Headings

  • Smoking
  • SARS-CoV-2
  • Risk Factors
  • Respiratory Mucosa
  • Quantitative Trait Loci
  • Pulmonary Disease, Chronic Obstructive
  • Obesity
  • Middle Aged
  • Humans
  • Genetic Variation
 

Citation

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Kasela, S., Ortega, V. E., Martorella, M., Garudadri, S., Nguyen, J., Ampleford, E., … Christenson, S. A. (2021). Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium. Genome Med, 13(1), 66. https://doi.org/10.1186/s13073-021-00866-2
Kasela, Silva, Victor E. Ortega, Molly Martorella, Suresh Garudadri, Jenna Nguyen, Elizabeth Ampleford, Anu Pasanen, et al. “Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium.Genome Med 13, no. 1 (April 21, 2021): 66. https://doi.org/10.1186/s13073-021-00866-2.
Kasela S, Ortega VE, Martorella M, Garudadri S, Nguyen J, Ampleford E, et al. Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium. Genome Med. 2021 Apr 21;13(1):66.
Kasela, Silva, et al. “Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium.Genome Med, vol. 13, no. 1, Apr. 2021, p. 66. Pubmed, doi:10.1186/s13073-021-00866-2.
Kasela S, Ortega VE, Martorella M, Garudadri S, Nguyen J, Ampleford E, Pasanen A, Nerella S, Buschur KL, Barjaktarevic IZ, Barr RG, Bleecker ER, Bowler RP, Comellas AP, Cooper CB, Couper DJ, Criner GJ, Curtis JL, Han MK, Hansel NN, Hoffman EA, Kaner RJ, Krishnan JA, Martinez FJ, McDonald M-LN, Meyers DA, Paine R, Peters SP, Castro M, Denlinger LC, Erzurum SC, Fahy JV, Israel E, Jarjour NN, Levy BD, Li X, Moore WC, Wenzel SE, Zein J, NHLBI SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS), NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Langelier C, Woodruff PG, Lappalainen T, Christenson SA. Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium. Genome Med. 2021 Apr 21;13(1):66.
Journal cover image

Published In

Genome Med

DOI

EISSN

1756-994X

Publication Date

April 21, 2021

Volume

13

Issue

1

Start / End Page

66

Location

England

Related Subject Headings

  • Smoking
  • SARS-CoV-2
  • Risk Factors
  • Respiratory Mucosa
  • Quantitative Trait Loci
  • Pulmonary Disease, Chronic Obstructive
  • Obesity
  • Middle Aged
  • Humans
  • Genetic Variation