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A comprehensive germline variant and expression analyses of ACE2, TMPRSS2 and SARS-CoV-2 activator FURIN genes from the Middle East: Combating SARS-CoV-2 with precision medicine

View ORCID ProfileFahd Al-Mulla, Anwar Mohammad, Ashraf Al Madhoun, Dania Haddad, Hamad Ali, View ORCID ProfileMuthukrishnan Eaaswarkhanth, Sumi Elsa John, Rasheeba Nizam, Arshad Channanath, Mohamed Abu-Farha, Rasheed Ahmad, Jehad Abubaker, Thangavel Alphonse Thanaraj
doi: https://doi.org/10.1101/2020.05.16.099176
Fahd Al-Mulla
1Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait
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  • For correspondence: fahd.almulla@dasmaninstitute.org
Anwar Mohammad
2Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait
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Ashraf Al Madhoun
3Department of Animal and Imaging Core Facilities, Dasman Diabetes Institute, Kuwait
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Dania Haddad
1Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait
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Hamad Ali
1Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait
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Muthukrishnan Eaaswarkhanth
1Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait
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  • ORCID record for Muthukrishnan Eaaswarkhanth
Sumi Elsa John
1Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait
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Rasheeba Nizam
1Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait
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Arshad Channanath
1Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait
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Mohamed Abu-Farha
4Department of Special Services Facilities, Dasman Diabetes Institute, Kuwait
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Rasheed Ahmad
5Department of Immunology & Microbiology, Dasman Diabetes Institute, Kuwait
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Jehad Abubaker
2Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait
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Thangavel Alphonse Thanaraj
1Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait
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Abstract

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 Statement

The authors have declared no competing interest.

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Posted May 16, 2020.
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A comprehensive germline variant and expression analyses of ACE2, TMPRSS2 and SARS-CoV-2 activator FURIN genes from the Middle East: Combating SARS-CoV-2 with precision medicine
Fahd Al-Mulla, Anwar Mohammad, Ashraf Al Madhoun, Dania Haddad, Hamad Ali, Muthukrishnan Eaaswarkhanth, Sumi Elsa John, Rasheeba Nizam, Arshad Channanath, Mohamed Abu-Farha, Rasheed Ahmad, Jehad Abubaker, Thangavel Alphonse Thanaraj
bioRxiv 2020.05.16.099176; doi: https://doi.org/10.1101/2020.05.16.099176
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A comprehensive germline variant and expression analyses of ACE2, TMPRSS2 and SARS-CoV-2 activator FURIN genes from the Middle East: Combating SARS-CoV-2 with precision medicine
Fahd Al-Mulla, Anwar Mohammad, Ashraf Al Madhoun, Dania Haddad, Hamad Ali, Muthukrishnan Eaaswarkhanth, Sumi Elsa John, Rasheeba Nizam, Arshad Channanath, Mohamed Abu-Farha, Rasheed Ahmad, Jehad Abubaker, Thangavel Alphonse Thanaraj
bioRxiv 2020.05.16.099176; doi: https://doi.org/10.1101/2020.05.16.099176

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