Understand Variability of COVID-19 Through Population and Tissue Variations in Expression of SARS-CoV-2 Host Genes

Abstract

An urgent question of coronavirus disease 2019 (COVID-19) is population variation in susceptibility to SARS-CoV-2 infection and symptom severity. We explore the expression profiles of SARS-CoV-2 host genes, their variations, age- and sex-dependency in the normal population. Genes exhibiting most variable expression include ACE2, CLEC4G, CLEC4M, CD209 (interact with the SARS-CoV-2 spike protein); REEP6 (a receptor accessory protein expressed in the olfactory epithelium); SLC27A2 and PKP2 (inhibit virus replication); and PTGS2 (mediates fever response). Analysis of genetic variants associated with host gene expression suggests a genetic contribution to phenotypic variations in multiple organs upon virus attack. SNP rs4804803, associated with SARS severity, affects expression of CLEC4G and CD209. Genetic variations of TMPRSS2, CTSB, and CTSL (proteases associated with SARS-CoV-2 entry) contribute to their expression variations. The most significant age-dependent gene is ACE2, the cellular receptor of SARS-CoV-2. Others include TGF-β family member GDF15, mediating inflammation, and VKORC1, possibly explaining vitamin K deficiency in COVID-19. TIMM10 and ERGIC1 exhibit significant sex differences. Based on the hypothesis that perturbing host gene expression presents a strategy for COVID-19 treatment, we identified antiviral drug ribavirin, among others, as putative treatment candidates for further investigation.Funding: This work has been supported by the National Institutes of Health [grant number R01GM137428 to L.C., R01MH116220 and R01NS104041 to S.Z.].Declaration of Interest: The authors declare no competing interests.Ethical Approval: Not Applicable.