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

Kasela, S.; Ortega, V. E.; Martorella, M.; Garudadri, S.; Nguyen, J.; Ampleford, E.; Pasanen, A.; Nerella, S.; Buschur, K. L.; Barjaktarevic, I. Z.; Barr, R. G.; Bleecker, E. R.; Bowler, R. P.; Comellas, A. P.; Cooper, C. B.; Couper, D. J.; Criner, G. J.; Curtis, J. L.; Han, M. K.; Hansel, N. N.; Hoffman, E. A.; Kaner, R. J.; Krishnan, J. A.; Martinez, F. J.; McDonald, M.-L. N.; Meyers, D. A.; Paine, R.; Peters, S. P.; Castro, M.; Denlinger, L. C.; Erzurum, S. C.; Fahy, J. V.; Israel, E.; Jarjour, N. N.; Levy, B. D.; Li, X.; Moore, W. C.; Wenzel, S. E.; Zein, J.; InteR, NHLBI SubPopulations and

Particular host and environmental factors influence susceptibility to severe COVID-19. We analyzed RNA-sequencing data from bronchial epithelial brushings - a relevant tissue for SARS-CoV-2 infection - obtained from three cohorts of uninfected individuals, and investigated how non-genetic and genetic factors affect the regulation of host genes implicated in COVID-19. 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. 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.