Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium
Authors:   NHLBI SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS), Kasela Silva ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Ortega Victor E. , Martorella Molly , Garudadri Suresh , Nguyen Jenna , Ampleford Elizabeth , Pasanen Anu , Nerella Srilaxmi , Buschur Kristina L. , Barjaktarevic Igor Z. , Barr R. Graham , Bleecker Eugene R. , Bowler Russell P. , Comellas Alejandro P. , Cooper Christopher B. , Couper David J. , Criner Gerard J. , Curtis Jeffrey L. , Han MeiLan K. , Hansel Nadia N. , Hoffman Eric A. , Kaner Robert J. , Krishnan Jerry A. , Martinez Fernando J. , McDonald Merry-Lynn N. , Meyers Deborah A. , Paine Robert , Peters Stephen P. , Castro Mario , Denlinger Loren C. , Erzurum Serpil C. , Fahy John V. , Israel Elliot , Jarjour Nizar N. , Levy Bruce D. , Li Xingnan , Moore Wendy C. , Wenzel Sally E. , Zein Joe , Langelier Charles , Woodruff Prescott G. , Lappalainen Tuuli , Christenson Stephanie A. 
Published: April 2021

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.