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

TitleGenetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium.
Publication TypePublication
Year2021
AuthorsKasela S, Ortega VE, Martorella M, Garudadri S, Nguyen J, Ampleford E, Pasanen A, Nerella S, Buschur KL, Barjaktarevic IZ, R Barr G, 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, Langelier C, Woodruff PG, Lappalainen T, Christenson SA
Corporate AuthorsNHLBI SubPopulations and InteRmediate Outcome Measures In COPD Study(SPIROMICS), NHLBI Trans-Omics for Precision Medicine(TOPMed) Consortium
JournalGenome Med
Volume13
Issue1
Pagination66
Date Published2021 04 21
ISSN1756-994X
KeywordsAdult, Aged, Aged, 80 and over, Angiotensin-Converting Enzyme 2, asthma, Bronchi, Cardiovascular Diseases, COVID-19, Gene Expression, Genetic Variation, Humans, Middle Aged, Obesity, Pulmonary Disease, Chronic Obstructive, Quantitative Trait Loci, Respiratory Mucosa, Risk Factors, SARS-CoV-2, smoking
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.

DOI10.1186/s13073-021-00866-2
Alternate JournalGenome Med
PubMed ID33883027
PubMed Central IDPMC8059115
Grant ListR01HL142992 / HL / NHLBI NIH HHS / United States
K01 AG059898 / AG / NIA NIH HHS / United States
P01 HL107202 / HL / NHLBI NIH HHS / United States
R01GM122924 / GM / NIGMS NIH HHS / United States
R01HL121774 / HL / NHLBI NIH HHS / United States
U01 HL137880 / HL / NHLBI NIH HHS / United States
U01HL137880 / HL / NHLBI NIH HHS / United States
F30HG011194 / HG / NHGRI NIH HHS / United States
K23 HL138461 / HL / NHLBI NIH HHS / United States
P30 ES010126 / ES / NIEHS NIH HHS / United States
R01MH106842 / MH / NIMH NIH HHS / United States
T32 HL144442 / HL / NHLBI NIH HHS / United States
K23HL123778 / HL / NHLBI NIH HHS / United States
R01HL142028 / HL / NHLBI NIH HHS / United States
R01GM124486 / GM / NIGMS NIH HHS / United States
R01HL137880 / HL / NHLBI NIH HHS / United States
K23 HL123778 / HL / NHLBI NIH HHS / United States
K24 HL137013 / HL / NHLBI NIH HHS / United States
T32HL144442 / HL / NHLBI NIH HHS / United States
K08 HL141601 / HL / NHLBI NIH HHS / United States
UM1HG008901 / HG / NHGRI NIH HHS / United States
U19 AI077439 / AI / NIAID NIH HHS / United States
R01 HL142028 / HL / NHLBI NIH HHS / United States
MS#: 
MS242
Manuscript Full Title: 
Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium.
Manuscript Lead/Corresponding Author Affiliation: 
Clinical Center: San Francisco (University of California at San Francisco)
ECI: 
Manuscript Status: 
Published and Public