Imperial College London
Alternate

ProfessorMichaelSternberg

Faculty of Natural Sciences, Department of Life Sciences

Director, Systems Biology and Bioinformatics Centre
 
 
 
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Contact

 

+44 (0)20 7594 5212m.sternberg Website

 
 
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Location

 

306Sir Ernst Chain BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{David:2022:10.1016/j.retram.2022.103333,
author = {David, A and Parkinson, N and Peacock, TP and Pairo-Castineira, E and Khanna, T and Cobat, A and Tenesa, A and Sancho-Shimizu, V and Casanova, J-L and Abel, L and Barclay, WS and Baillie, JK and Sternberg, MJE},
doi = {10.1016/j.retram.2022.103333},
journal = {Current Research in Translational Medicine},
title = {A common TMPRSS2 variant has a protective effect against severe COVID-19},
url = {http://dx.doi.org/10.1016/j.retram.2022.103333},
volume = {70},
year = {2022}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Background: The human protein transmembrane protease serine type 2 (TMPRSS2) plays a key role in SARS-CoV-2 infection, as it is required to activate the virus’ spike protein, facilitating entry into target cells. We hypothesized that naturally-occurring TMPRSS2 human genetic variants affecting the structure and function of the TMPRSS2 protein may modulate the severity of SARS-CoV-2 infection.Methods: We focused on the only common TMPRSS2 non-synonymous variant predicted to be damaging (rs12329760 C>T, p.V160M), which has a minor allele frequency ranging from from 0.14 in Ashkenazi Jewish to 0.38 in East Asians. We analysed the association between the rs12329760 and COVID-19 severity in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units recruited as part of the GenOMICC (Genetics Of Mortality In Critical Care) study. Logistic regression analyses were adjusted for sex, age and deprivation index. For in vitro studies, HEK293 cells were co-transfected with ACE2 and either TMPRSS2 wild type or mutant (TMPRSS2V160M). A SARS-CoV-2 pseudovirus entry assay was used to investigate the ability of TMPRSS2V160M to promote viral entry.Results: We show that the T allele of rs12329760 is associated with a reduced likelihood of developing severe COVID-19 (OR 0.87, 95%CI:0.79-0.97, p=0.01). This association was stronger in homozygous individuals when compared to the general population (OR 0.65, 95%CI:0.50-0.84, p=1.3×10−3). We demonstrate in vitro that this variant, which causes the amino acid substitution valine to methionine, affects the catalytic activity of TMPRSS2 and is less able to support SARS-CoV-2 spike-mediated entry into cells.Conclusion: TMPRSS2 rs12329760 is a common variant associated with a significantly decreased risk of severe COVID-19. Further studies are needed to assess the expression of TMPRSS2 across different age groups. Moreover, our results identify TMPRSS2 as a promising drug target, with a potential role for
AU  - David,A
AU  - Parkinson,N
AU  - Peacock,TP
AU  - Pairo-Castineira,E
AU  - Khanna,T
AU  - Cobat,A
AU  - Tenesa,A
AU  - Sancho-Shimizu,V
AU  - Casanova,J-L
AU  - Abel,L
AU  - Barclay,WS
AU  - Baillie,JK
AU  - Sternberg,MJE
DO  - 10.1016/j.retram.2022.103333
PY  - 2022///
SN  - 2452-3186
TI  - A common TMPRSS2 variant has a protective effect against severe COVID-19
T2  - Current Research in Translational Medicine
UR  - http://dx.doi.org/10.1016/j.retram.2022.103333
UR  - https://www.sciencedirect.com/science/article/pii/S2452318622000010?via%3Dihub
UR  - http://hdl.handle.net/10044/1/93916
VL  - 70
ER  -
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