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

International audienceThe 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 2,244critically 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 ofTMPRSS2V160M to promote viral entry. Results: We show that the T allele of rs12329760 is associated with a reduced likelihood of developing severeCOVID-19 (OR 0.87, 95%CI:0.79−0.97, p = 0.01). This association was stronger in homozygous individualswhen compared to the general population (OR 0.65, 95%CI:0.50−0.84, p = 1.3 £ 103). We demonstrate invitro that this variant, which causes the amino acid substitution valine to methionine, affects the catalyticactivity 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 ofsevere COVID-19. Further studies are needed to assess the expression of TMPRSS2 across different agegroups. Moreover, our results identify TMPRSS2 as a promising drug target, with a potential role for camostatmesilate, a drug approved for the treatment of chronic pancreatitis and postoperative reflux esophagitis, inthe treatment of COVID-19. Clinical trials are needed to confirm this