A common TMPRSS2 variant has a protective effect against severe COVID-19.

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 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 (TMPRSS2

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

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 camostat mesilate, a drug approved for the treatment of chronic pancreatitis and postoperative reflux esophagitis, in the treatment of COVID-19. Clinical trials are needed to confirm this.

Informations de copyright

Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Competing Interest Dr. David reports grants from Wellcome Trust during the conduct of the study; Dr. Parkinson reports grants from Wellcome Trust during the conduct of the study; Dr. Peacock reports grants from MRC/UKRI, grants from BBSRC during the conduct of the study; Dr. Pairo-Castineira has nothing to disclose. Dr. Khanna reports grants from BBSRC during the conduct of the study; Dr. Cobat has nothing to disclose. Dr. Tenesa reports grants from BBSRC, grants from Health Data Research UK during the conduct of the study. Dr. Sancho-Shimizu reports grants from UKRI Future Leader's Fellowship during the conduct of the study; Dr. Casanova reports other from Howard Hughes Medical Institute, other from Rockefeller University, other from St. Giles Foundation, other from Fisher centre for Alzheimer's Research Foundation, other from Meyer Foundation, other from Square Foundation, other from Grandir - Fonds de solidarité pour l'enfance, other from SCOR Corporate Foundation for Science, other from Institut National de la Santé et de la Recherche Médicale (INSERM), other from University of Paris, other from National Institutes of Health (NIH), other from French Foundation for Medical Research (FRM), other from FRM and French National Research Agency (ANR) GENCOVID project during the conduct of the study; Dr. Abel reports other from Agence Nationale de la Recherche during the conduct of the study; Dr. Barclay reports grants from BBSRC during the conduct of the study; Dr. Baillie has nothing to disclose. Dr. Sternberg reports grants from Wellcome Trust, grants from BBSRC, during the conduct of the study.