Evidence map›Paper›PMID 33883027›Full record

ArticleGenome medicine2021

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 and 35 more

Registry-linked trialOpen access · goldAbstract readMulticenter Study
PubMed Full text at PMC Publisher
In one paragraph

Article in Genome medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT01969344 (Subpopulations and Intermediate Outcome Measures in COPD Study), which is not on this map. Cited by 26 papers.

0numbers the graph read from it
0cells of the map it votes in
26citing papers in PubMed
4.7field-weighted citation impact, top 4% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT01969344 active not recruitingnot on this map

Subpopulations and Intermediate Outcome Measures in COPD Study

TypeobservationalSponsorUniversity of North Carolina, Chapel HillRan2010 to 2031Enrolled2,981ConditionsCOPD, Chronic Obstructive Pulmonary Disease, Chronic Bronchitis, Emphysema
3 · Its place in the literature

Who cites it

26 citing papers in PubMed, 37 citations in OpenAlex.

  1. Article
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  7. Dysanapsis Genetic Risk Predicts Lung Function Across the Lifespan.American journal of respiratory and critical care medicine · 2024
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  10. Genetic analyses of chr11p15.5 region identifyThe Journal of asthma : official journal of the Association for the Care of Asthma · 2023
    Article
  11. Article
  12. Review
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  14. Article
  15. Low CC16 mRNA Expression Levels in Bronchial Epithelial Cells Are Associated with Asthma Severity.American journal of respiratory and critical care medicine · 2023
    Article
  16. Article
  17. Article
  18. Article
  19. Article
  20. COVID-19 Infections and Asthma.The journal of allergy and clinical immunology. In practice · 2022
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

45 authors at 17 institutions in 1 country.

Silva KaselaNew York Genome Center, New York, NY, USA. skasela@nygenome.org.ORCID 0000-0003-4362-0034
Victor E OrtegaDepartment of Internal Medicine, Section of Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Molly MartorellaNew York Genome Center, New York, NY, USA.
Suresh GarudadriDepartment of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Jenna NguyenDivision of Pulmonary, Critical Care, Allergy, & Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
Elizabeth AmplefordDepartment of Internal Medicine, Section of Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Anu PasanenNew York Genome Center, New York, NY, USA.
Srilaxmi NerellaDivision of Pulmonary, Critical Care, Allergy, & Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
Kristina L BuschurNew York Genome Center, New York, NY, USA.
Igor Z BarjaktarevicDivision of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
R Graham BarrDepartment of Medicine, Columbia University Medical Center, New York, NY, USA.
Eugene R BleeckerDivision of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, Tucson, AZ, USA.
Russell P BowlerDivision of Pulmonary Medicine, Department of Medicine, National Jewish Health, Denver, CO, USA.
Alejandro P ComellasDivision of Pulmonary and Critical Care, University of Iowa, Iowa City, IA, USA.
Christopher B CooperDivision of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
David J CouperDepartment of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Gerard J CrinerDepartment of Thoracic Medicine and Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.
Jeffrey L CurtisDivision of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Health System, Ann Arbor, MI, USA.
MeiLan K HanDivision of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Health System, Ann Arbor, MI, USA.
Nadia N HanselDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Eric A HoffmanDivision of Physiologic Imaging, Department of Radiology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
Robert J KanerDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Weill Cornell Medicine, New York, NY, USA.
Jerry A KrishnanDivision of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois at Chicago, Chicago, IL, USA.
Fernando J MartinezDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Weill Cornell Medicine, New York, NY, USA.
Merry-Lynn N McDonaldDivision of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Deborah A MeyersDivision of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, Tucson, AZ, USA.
Robert PaineDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
Stephen P PetersDepartment of Internal Medicine, Section of Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Mario CastroDivision of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Kansas School of Medicine, Kansas City, KS, USA.
Loren C DenlingerDivision of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
Serpil C ErzurumDepartment of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
John V FahyDivision of Pulmonary, Critical Care, Allergy, & Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
Elliot IsraelDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Nizar N JarjourDivision of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
Bruce D LevyDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Xingnan LiDivision of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, Tucson, AZ, USA.
Wendy C MooreDepartment of Internal Medicine, Section of Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Sally E WenzelDepartment of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
Joe ZeinRespiratory Institute, Cleveland Clinic, Cleveland, OH, USA.
NHLBI SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS)
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Charles LangelierDivision of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA.
Prescott G WoodruffDivision of Pulmonary, Critical Care, Allergy, & Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
Tuuli Lappalainen *New York Genome Center, New York, NY, USA. tlappalainen@nygenome.org.
Stephanie A Christenson *Division of Pulmonary, Critical Care, Allergy, & Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA. stephanie.christenson@ucsf.edu.
University of California, San Francisco · USUniversity of Arizona · USBrigham and Women's Hospital · USCornell University · USNew York Genome Center · USCleveland Clinic · USJohns Hopkins University · USUniversity of California, Los Angeles · USUniversity of Iowa · USUniversity of North Carolina at Chapel Hill · USUniversity of Wisconsin–Madison · USMichigan Medicine · USUniversity of Kansas · USUniversity of Pittsburgh · USUniversity of Utah · USVA Ann Arbor Healthcare System · USWake Forest University · US

Funding

New York Center for Collaborative Research In Common Disease Genomics: Genome Aggregation and Joint Variant Calling for CCDG Freeze2UM1HG008901 · NHGRI · NEW YORK GENOME CENTER · PI MANIATIS, THOMAS P, WIGLER, MICHAEL H · 2016 to 2020
$56.6M
Understanding Asthma EndotypesU19AI077439 · NIAID · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Nirav Rati Bhakta · 2008 to 2026
$41.1M
Pulmonary Toxicology Facility CoreP30ES005605 · NIEHS · UNIVERSITY OF IOWA · PI Brandi Janssen · 1990 to 2026
$40.5M
UNC-CH CENTER FOR ENVIRONMENTAL HEALTH &SUSCEPTIBILITYP30ES010126 · NIEHS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Melissa A. Troester · 2001 to 2026
$36.3M
SPIROMICS II: Biological underpinnings of COPD heterogeneity and progressionU01HL137880 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI WOODRUFF, PRESCOTT G · 2017 to 2021
$27.9M
Role of miRNAs in Th2-Driven inflammation in AsthmaP01HL107202 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI ANSEL, KARL MARK · 2012 to 2023
$23.3M
Studies of Rare Genetic Variation in the Isolated Population of SardiniaR01HL117626 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI ABECASIS, GONCALO · 2013 to 2016
$10.5M
Rare variants and NHLBI traits in deeply phenotyped cohortsR01HL120393 · NHLBI · UNIVERSITY OF WASHINGTON · PI PSATY, BRUCE M, RICE, KENNETH M. · 2014 to 2016
$8.9M
SPIROMICS GIC SupportU24HL141762 · NHLBI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI COUPER, DAVID J, O'NEAL, WANDA K · 2018 to 2022
$7.2M
Rare variants and NHLBI traits in deeply phenotyped cohortsU01HL120393 · NHLBI · UNIVERSITY OF WASHINGTON · PI PSATY, BRUCE M, RICE, KENNETH M. · 2017 to 2018
$5.6M
Statistical models for fine-mapping and interpretation of schizophrenia-associated lociR01MH106842 · NIMH · NEW YORK GENOME CENTER · PI BUSSEMAKER, HARMEN J, LAPPALAINEN, TUULI · 2015 to 2024
$5.0M
Effects of Rare Variants and Ancestry on Beta Agonist Response in Asthma and COPDR01HL142992 · NHLBI · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI ORTEGA, VICTOR E. · 2019 to 2023
$3.7M
NHGRI NIH HHS F30 HG011194NHGRI NIH HHS F30HG011194NHGRI NIH HHS UM1 HG008901NHGRI NIH HHS UM1HG008901NHLBI NIH HHS HHSN268200900013CNHLBI NIH HHS HHSN268200900014CNHLBI NIH HHS HHSN268200900015CNHLBI NIH HHS HHSN268200900016CNHLBI NIH HHS HHSN268200900017CNHLBI NIH HHS HHSN268200900018CNHLBI NIH HHS HHSN268200900019CNHLBI NIH HHS HHSN268200900020CNHLBI NIH HHS HHSN268201800001CNHLBI NIH HHS K08 HL141601NHLBI NIH HHS K23 HL123778NHLBI NIH HHS K23HL123778NHLBI NIH HHS K23 HL138461NHLBI NIH HHS K24 HL137013NHLBI NIH HHS P01 HL107202NHLBI NIH HHS R01 HL117626NHLBI NIH HHS R01 HL120393NHLBI NIH HHS R01 HL121774NHLBI NIH HHS R01HL121774NHLBI NIH HHS R01HL137880NHLBI NIH HHS R01 HL142028NHLBI NIH HHS R01HL142028NHLBI NIH HHS R01 HL142992NHLBI NIH HHS R01HL142992NHLBI NIH HHS T32 HL144442NHLBI NIH HHS T32HL144442NHLBI NIH HHS U01 HL120393NHLBI NIH HHS U01 HL137880NHLBI NIH HHS U01HL137880NHLBI NIH HHS U24 HL141762NIAID NIH HHS R01 AI129958NIAID NIH HHS U19 AI077439NIA NIH HHS K01 AG059898NIEHS NIH HHS P30 ES005605NIEHS NIH HHS P30 ES010126NIGMS NIH HHS R01 GM122924NIGMS NIH HHS R01GM122924NIGMS NIH HHS R01 GM124486NIGMS NIH HHS R01GM124486NIMH NIH HHS R01 MH106842NIMH NIH HHS R01MH106842
6 · The paper itself

Abstract

backgroundThe 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.

methodsWe 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.

resultsWe 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.

conclusionsThese 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.

Indexed as

BronchiRespiratory MucosaSARS-CoV-2AdultAgedAged, 80 and overAngiotensin-Converting Enzyme 2AsthmaCardiovascular DiseasesCOVID-19Gene ExpressionGenetic VariationHumansMiddle AgedObesityPulmonary Disease, Chronic ObstructiveACE2 protein, humanAngiotensin-Converting Enzyme 2ACE2Bronchial epitheliumCOVID-19eQTLSARS-CoV-2

Identifiers

PMID33883027
PMCPMC8059115
OpenAlexW3089895762

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.