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

Alessia David, Nicholas Parkinson, Thomas P Peacock, Erola Pairo-Castineira, Tarun Khanna, Aurelie Cobat, Albert Tenesa, Vanessa Sancho-Shimizu, Jean-Laurent Casanova, Laurent Abel, Wendy S. Barclay, J Kenneth Baillie, Michael J E Sternberg

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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 V160M). A SARS-CoV-2 pseudovirus entry assay was used to investigate the ability of TMPRSS2 V160M 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 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.

Original languageEnglish
Article number103333
JournalCurrent Research in Translational Medicine
Volume70
Issue number2
Early online date10 Jan 2022
DOIs
Publication statusPublished - May 2022

Keywords / Materials (for Non-textual outputs)

  • COVID-19
  • COVID19 severity
  • SARS-CoV-2
  • TMPRSS2
  • Targeting the host to prevent

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