Abstract
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 (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 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.
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 (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 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 language | English |
|---|---|
| Article number | 103333 |
| Number of pages | 21 |
| Journal | Current Research in Translational Medicine |
| Volume | 70 |
| Issue number | 2 |
| Early online date | 10 Jan 2022 |
| DOIs | |
| Publication status | Published - May 2022 |
Bibliographical note
Funding:Wellcome Trust, BBSRC, UKRI Future Leader's Fellowship, Health Data Research UK
AD and NP were supported by the Wellcome Trust (grants 104,955/Z/14/Z, 218,242/Z/19/Z and 211,496/Z/18/Z) and TK by the BBSRC (grants BB/P011705/1 and BB/P023959/1), VSS is supported by UKRI Future Leader's Fellowship (MR/S032304/1), J-LC is supported by Howard Hughes Medical Institute, Rockefeller University, St. Giles Foundation, Fisher centre for Alzheimer's Research Foundation, Meyer Foundation, Square Foundation, Grandir - Fonds de solidarité pour l'enfance, SCOR Corporate Foundation for Science, Institut National de la Santé et de la Recherche Médicale (INSERM), University of Paris, National Institutes of Health (R01AI088364), French Foundation for Medical Research (EQU201903007798), FRM and French National Research Agency (ANR) GENCOVID project (ANR-20-COVI-0003); LA is supported by the Agence Nationale de la Recherche (ANR-10-IAHU-01, ANR-10-LABX-62-IBEID), TPP and WSB are supported by BBSRC grants BB/R013071/1 and BBSRC and the G2P-UK National Virology consortium (funded by MRC/UKRI, grant ref: MR/W005611/1), AT was supported by Roslin Institute Strategic Programme Grants from the BBSRC (BBS/E/D/10,002,070 and BBS/E/D/30,002,275) and Health Data Research UK (references HDR-9004 and HDR-9003).
Keywords
- SARS-CoV-2
- COVID-19
- TMPRSS2
- Targeting the host to prevent
- COVID19 severity