A Common TMPRSS2 Variant Protects 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 T to C, p.V160M), which has a minor allele frequency of ~25% in the population. We analysed the association between the rs12329760 and COVID19 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 TMPRSS2V160M ability to promote viral entry. Findings: We show that the T allele of rs12329760 is associated with a reduced likelihood of developing severe COVID19 (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, impacts the catalytic activity of TMPRSS2 and is less able to support SARS-CoV-2 spike-mediated entry into cells. Interpretation: TMPRSS2 rs12329760 is a common variant associated with a significantly decreased risk of severe COVID19. Further studies are needed to assess the expression of the 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 COVID19. Clinical trials are needed to confirm this. Funding: Wellcome Trust, BBSRC, UKRI Future Leader’s Fellowship, Health Data Research UK Declaration of Interests: On behalf of all authors, the corresponding author states that there is no conflict of interest. Ethics Approval Statement: Research ethics committees (Scotland 15/SS/0110, England, Wales and Northern Ireland: 19/WM/0247).