RT Journal Article
SR Electronic
T1 A comprehensive germline variant and expression analyses of <em>ACE2</em>, <em>TMPRSS2</em> and SARS-CoV-2 activator <em>FURIN</em> genes from the Middle East: Combating SARS-CoV-2 with precision medicine
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.05.16.099176
DO 10.1101/2020.05.16.099176
A1 Fahd Al-Mulla
A1 Anwar Mohammad
A1 Ashraf Al Madhoun
A1 Dania Haddad
A1 Hamad Ali
A1 Muthukrishnan Eaaswarkhanth
A1 Sumi Elsa John
A1 Rasheeba Nizam
A1 Arshad Channanath
A1 Mohamed Abu-Farha
A1 Rasheed Ahmad
A1 Jehad Abubaker
A1 Thangavel Alphonse Thanaraj
YR 2020
UL http://biorxiv.org/content/early/2020/05/16/2020.05.16.099176.abstract
AB 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 uses ACE2 as a cell receptor, TMPRSS2 protease, and FURIN peptidase 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 the ACE2, TMPRSS2, and FURIN genes. We identified two activating variants (K26R and N720D) in the ACE2 gene that are more common in Europeans than in the Middle Eastern, East Asian, and African populations. We postulate that K26R can activate ACE2 and facilitate binding to S-protein RBD while N720D enhances TMPRSS2 cutting and, ultimately, viral entry. We also detected deleterious variants in FURIN that are frequent in the Middle Eastern but not in the European populations. This study highlights specific genetic variations in the ACE2 and FURIN genes 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 between ACE2 variants identified in people from Middle Eastern origins that can be further explored to explain the variation in COVID-19 infection and mortality rates globally.Competing Interest StatementThe authors have declared no competing interest.