Genome Medicine (Apr 2021)
Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium
- Silva Kasela,
- Victor E. Ortega,
- Molly Martorella,
- Suresh Garudadri,
- Jenna Nguyen,
- Elizabeth Ampleford,
- Anu Pasanen,
- Srilaxmi Nerella,
- Kristina L. Buschur,
- Igor Z. Barjaktarevic,
- R. Graham Barr,
- Eugene R. Bleecker,
- Russell P. Bowler,
- Alejandro P. Comellas,
- Christopher B. Cooper,
- David J. Couper,
- Gerard J. Criner,
- Jeffrey L. Curtis,
- MeiLan K. Han,
- Nadia N. Hansel,
- Eric A. Hoffman,
- Robert J. Kaner,
- Jerry A. Krishnan,
- Fernando J. Martinez,
- Merry-Lynn N. McDonald,
- Deborah A. Meyers,
- Robert Paine,
- Stephen P. Peters,
- Mario Castro,
- Loren C. Denlinger,
- Serpil C. Erzurum,
- John V. Fahy,
- Elliot Israel,
- Nizar N. Jarjour,
- Bruce D. Levy,
- Xingnan Li,
- Wendy C. Moore,
- Sally E. Wenzel,
- Joe Zein,
- NHLBI SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS),
- NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium,
- Charles Langelier,
- Prescott G. Woodruff,
- Tuuli Lappalainen,
- Stephanie A. Christenson
Affiliations
- Silva Kasela
- New York Genome Center
- Victor E. Ortega
- Department of Internal Medicine, Section of Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine
- Molly Martorella
- New York Genome Center
- Suresh Garudadri
- Department of Medicine, Stanford University School of Medicine
- Jenna Nguyen
- Division of Pulmonary, Critical Care, Allergy, & Sleep Medicine, Department of Medicine, University of California San Francisco
- Elizabeth Ampleford
- Department of Internal Medicine, Section of Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine
- Anu Pasanen
- New York Genome Center
- Srilaxmi Nerella
- Division of Pulmonary, Critical Care, Allergy, & Sleep Medicine, Department of Medicine, University of California San Francisco
- Kristina L. Buschur
- New York Genome Center
- Igor Z. Barjaktarevic
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles
- R. Graham Barr
- Department of Medicine, Columbia University Medical Center
- Eugene R. Bleecker
- Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona
- Russell P. Bowler
- Division of Pulmonary Medicine, Department of Medicine, National Jewish Health
- Alejandro P. Comellas
- Division of Pulmonary and Critical Care, University of Iowa
- Christopher B. Cooper
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles
- David J. Couper
- Department of Biostatistics, University of North Carolina at Chapel Hill
- Gerard J. Criner
- Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine at Temple University
- Jeffrey L. Curtis
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Health System
- MeiLan K. Han
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Health System
- Nadia N. Hansel
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine
- Eric A. Hoffman
- Division of Physiologic Imaging, Department of Radiology, University of Iowa Hospitals and Clinics
- Robert J. Kaner
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Weill Cornell Medicine
- Jerry A. Krishnan
- Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois at Chicago
- Fernando J. Martinez
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Weill Cornell Medicine
- Merry-Lynn N. McDonald
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham
- Deborah A. Meyers
- Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona
- Robert Paine
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Utah
- Stephen P. Peters
- Department of Internal Medicine, Section of Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine
- Mario Castro
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Kansas School of Medicine
- Loren C. Denlinger
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, University of Wisconsin-Madison
- Serpil C. Erzurum
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic
- John V. Fahy
- Division of Pulmonary, Critical Care, Allergy, & Sleep Medicine, Department of Medicine, University of California San Francisco
- Elliot Israel
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital
- Nizar N. Jarjour
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, University of Wisconsin-Madison
- Bruce D. Levy
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital
- Xingnan Li
- Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona
- Wendy C. Moore
- Department of Internal Medicine, Section of Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine
- Sally E. Wenzel
- Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh
- Joe Zein
- Respiratory Institute, Cleveland Clinic
- NHLBI SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS)
- NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
- Charles Langelier
- Division of Infectious Diseases, University of California San Francisco
- Prescott G. Woodruff
- Division of Pulmonary, Critical Care, Allergy, & Sleep Medicine, Department of Medicine, University of California San Francisco
- Tuuli Lappalainen
- New York Genome Center
- Stephanie A. Christenson
- Division of Pulmonary, Critical Care, Allergy, & Sleep Medicine, Department of Medicine, University of California San Francisco
- DOI
- https://doi.org/10.1186/s13073-021-00866-2
- Journal volume & issue
-
Vol. 13,
no. 1
pp. 1 – 17
Abstract
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.
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