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AbstractThe SARS-CoV-2 pandemic has resulted in widespread morbidity and mortality globally.ACE2is a receptor for SARS-CoV-2 and differences in expression may affect susceptibility to COVID-19. Using HCV-infected liver tissue from 195 individuals, we discovered that among genes negatively correlated withACE2, interferon signalling pathways were highly enriched and observed down-regulation ofACE2after interferon-alpha treatment. Negative correlation was also found in the gastrointestinal tract and in lung tissue from a murine model of SARS-CoV-1 infection suggesting conserved regulation ofACE2across tissue and species. Performing a genome-wide eQTL analysis, we discovered that polymorphisms in the interferon lambda (IFNL) region are associated withACE2expression. IncreasedACE2expression in the liver was also associated with age and presence of cirrhosis. Polymorphisms in theIFNLregion may impact not only antiviral responses but alsoACE2with potential consequences for clinical outcomes in distinct ethnic groups and with implications for therapeutic interventions.

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