<ns3:p><ns3:bold>Background</ns3:bold>: Angiotensin I converting enzyme 2 (ACE2) is a receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and differences in its expression may affect susceptibility to infection.</ns3:p><ns3:p> <ns3:bold>Methods</ns3:bold>: We performed a genome-wide expression quantitative trait loci (eQTL) analysis using hepatitis C virus-infected liver tissue from 190 individuals.</ns3:p><ns3:p> <ns3:bold>Results</ns3:bold>: We discovered that polymorphism in a type III interferon gene (<ns3:italic>IFNL4</ns3:italic>), which eliminates IFN-λ4 production, is associated with a two-fold increase in ACE2 RNA expression. Conversely, among genes negatively correlated with <ns3:italic>ACE2 </ns3:italic>expression, IFN-signalling pathways were highly enriched and <ns3:italic>ACE2 </ns3:italic>was downregulated after IFN-α treatment. Negative correlation was also found in the gastrointestinal tract where inflammation driven IFN-stimulated genes were negatively correlated with <ns3:italic>ACE2</ns3:italic> expression and in lung tissue from a murine model of SARS-CoV-1 infection suggesting conserved regulation of <ns3:italic>ACE2 </ns3:italic>across tissue and species.</ns3:p><ns3:p> <ns3:bold>Conclusions</ns3:bold>: We conclude that <ns3:italic>ACE2 </ns3:italic>is likely a negatively-regulated interferon-stimulated gene (ISG) and carriage of <ns3:italic>IFNL4 </ns3:italic>gene alleles which modulates ISGs expression in viral infection may play a role in SARS-CoV-2 pathogenesis with implications for therapeutic interventions.</ns3:p>