A comprehensive germline variant and expression analyses ofACE2,TMPRSS2and SARS-CoV-2 activatorFURINgenes from the Middle East: Combating SARS-CoV-2 with precision medicine

The severity of the new COVID-19 pandemic caused by the SARS-CoV-2 virus is strikingly variable in different global populations. SARS-CoV-2 usesACE2as a cell receptor,TMPRSS2protease, andFURINpeptidase to invade human cells. Here, we investigated 1,378 whole-exome sequences of individuals from the Middle Eastern populations (Kuwait, Qatar, and Iran) to explore natural variations in theACE2,TMPRSS2,andFURINgenes. We identified two activating variants (K26R and N720D) in theACE2gene that are more common in Europeans than in the Middle Eastern, East Asian, and African populations. We postulate that K26R can activateACE2and facilitate binding to S-protein RBD while N720D enhancesTMPRSS2cutting and, ultimately, viral entry. We also detected deleterious variants inFURINthat are frequent in the Middle Eastern but not in the European populations. This study highlights specific genetic variations in theACE2andFURINgenes that may explain SARS-CoV-2 clinical disparity. We showed structural evidence of the functionality of these activating variants that increase the SARS-CoV-2 aggressiveness. Finally, our data illustrate a significant correlation betweenACE2variants identified in people from Middle Eastern origins that can be further explored to explain the variation in COVID-19 infection and mortality rates globally.