A point mutation in the wild type gene, V160M, has been shown to decrease the structural stability of TMPRSS2.  This variation, known as rs12329760, is reported to be more common in those with Indian ethnicity.  This finding may elucidate why Indians have experienced lower rates of infection.  

Missense rs12329760 Variation in the TMPRSS2 Gene Decreases Protein Stability

- identified gene expression profiles for TMPRSS2 using multiple large genome databases: GTEx portal, SNP nexus, and Ensembl genome project
- identified four key variants for expression of TMPRSS2 in lungs: rs464397, rs469390, rs2070788 and rs383510
- higher frequency of upregulating variants in European and American populations which may explain the variation in severity of SARS-CoV-2 infection

TMPRSS2 upregulating variants increasing SARS-CoV-2 infection in European and American populations

Because the incidence and mortality rates of COVID-19 are significantly different in different regions of the world, it is thought that human variation may play a greater role than viral variation in determining these outcomes.  Significant variation in the gene TMPRSS2, which codes for the protease TMPRSS2, has been observed in different ethnic groups.  This may contribute to the different rates of infectivity seen in different populations.  

Michigan State University

Smith College

TMPRSS2 is a human serine protease, an enzyme that cleaves a peptide chain via hydrolysis.  This enzyme has been shown to activate SARS-Cov-2 S protein by cleaving the S1 and S2 subunits of the S protein in order to expose the S2 subunit.  This allows the viral membrane to fuse with the cellular membrane.  Consequently, this process helps facilitate infection.  TMPRSS2 is also responsible for cleaving ACE2 receptors to further enhance SARS-CoV-2 entry.  This serine protease does not have a known, relevant function in human physiology and therefore could be a promising therapeutic target.  

TMPRSS2 in the Pathogenesis of COVID-19

Differences in COVID-19 inter-individual variability and lethality, along with differences among countries, raises the consideration of the role that predisposed genetics may play. Genetic variation may explain why some individuals without COVID-19 risk factors develop severe COVID-19.  Functional polymorphisms in the following genes are of interest due to their coded proteins' role in the pathogenesis of COVID-19:

- ACE2
- TMPRSS2

Understanding these variations in different populations could lead to more individualized treatment in COVID-19 patients.

Genetic Susceptibility to SARS-CoV-2 Infection in the Pathogenesis of COVID-19

Vishnubhotla, R., Vankadari, N., Ketavarapu, V., Amanchy, R., Avanthi, S., Bale, G., ... & Sasikala, M. (2020). Genetic variants in TMPRSS2 and Structure of SARS-CoV-2 spike glycoprotein and TMPRSS2 complex. bioRxiv. https://www.biorxiv.org/content/10.1101/2020.06.30.179663v1.full
doi: 10.1101/2020.06.30.179663

Genetic variants in TMPRSS2 and Structure of SARS-CoV-2 spike glycoprotein and TMPRSS2 complex

Four potential TMPRSS2 protease inhibitors were tested:

- Chemostat

- Upamostat

- Nafmostat

- Bromhexine hydrochloride

Each of these existing, clinically proven drugs were found to bind to the catalytic pocket of TMPRSS2 with high precision and specificity.  Theoretically, these drugs could impede SARS-CoV-2 S proteins from interacting with TMPRSS2 which would consequently influence infectivity.  This could be a hopeful target for antiviral drugs or a future vaccine.  

Using Serine Protease Inhibitors to Treat or Prevent COVID-19

Two potential TMPRSS2 binding sites on the SARS-CoV-2 spike protein have deep identified:

- Site 1: aa837 to aa 845

- Site 2: aa 976 to aa986

Both of these sites are located in the S2 subunit of the S protein.  As shown in this figure, these binding sites are largely homologous to those of SARS-CoV-1.

TMPRSS2 Binding Sites in SARS-CoV-2 S Protein

Genetic variation within the TMPRSS2 protease may play a role in COVID-19 infection

This graph displays the variance in the amount of TMPRSS2 expression there is in different types of tissues within the human body.

Graph of the Expression of TMPRSS2 in Various Tissues

- Arg and Lys residues within ACE2 amino acids 697-716 are required for cleavage
- Cleavage of ACE2 receptor might promote spike protein driven entry of the virus

TMPRSS2 Cleavage of ACE2

Schuler et al. demonstrated using both mouse and human cell lines that TMPRSS2 expression increased with age.  The regulation of the enzyme during development could contribute to why infants and children are less susceptible to severe COVID-19.  Hou et al. writes that is will be important to study age-related polymorphisms of TMPRSS2 in the future using genetic epidemiology methods.

Age-Related Polymorphisms of TMPRSS2

Hou et al. proposed three different models for treating COVID-19 based on three different phenotypes which are found in different populations.  The following drugs were used in the models:

- hydroxychloroquine
- E-64D (a protease inhibitor)
- camostat mesylate (a TMPRSS2 inhibitor approved in Japan for treating chronic pancreatitis) 

These pharmacogenomic models have yet to be tested and validated.  

Hypothesized Combination Therapies to Treat COVID-19 Based on Pharmacogenomics

This graphic shows the distribution of 61 potentially harmful ACE2 polymorphisms by population using variant assembly of databases, annotation of non-synonymous polymorphisms, and predictive-deleterious scoring. 
- databases: Genome Aggregation Database, Exome Sequencing Project, and 1000 Genomes Project (1KGP, www.internationalgenome.org)
- non-synonymous variant annotation: ANNOVAR
- deleterious assessment: CADD and Polyphen2 

The top bar shows ACE2 functional domains, and the vertical notches represents population counts of the respective variant. The heat map depicts polymorphism frequencies found within the different populations.

- 39% of variations occur in African/African-American (AFR) populations
- 54% of variations occur in non-Finnish European (EUR) populations
- Amish (AMI) and Ashkenazi Jewish (ASJ) populations do not appear to have any of these polymorphisms
- variants such as p.Arg514Gly may influence COVID-19 pathogenesis and its associated cardiovascular conditions by altering the AGT-ACE2 pathway

Population group legend: AFR, African/African-American; AMI, Amish; AMR, Latino/Admixed American; ASJ, Ashkenazi Jewish; EAS, East Asian; FIN, Finnish; EUR, Non-Finnish European; SAS, South Asian; PNA, population not assigned

Nonsynonymous ACE2 Variations by Population

This graphic shows the distribution of 63 potentially harmful TMPRSS2 polymorphisms by population using variant assembly of databases, annotation of non-synonymous polymorphisms, and predictive-deleterious scoring.

- databases: Genome Aggregation Database, Exome Sequencing Project, and 1000 Genomes Project (1KGP, www.internationalgenome.org)
- non-synonymous variant annotation: ANNOVAR
- deleterious assessment: CADD and Polyphen2

The top bar shows TMPRSS2 functional domains, and the vertical notches represents population counts of the respective variant. The heat map depicts polymorphism frequencies found within the different populations.

- 35% of variations occur in African/African-American (AFR) populations
- 59% of variations occur in non-Finnish European (EUR) populations
- all populations carry p.Val160Met (~25% allele frequency)
- p.Asp435Tyr, which codes for a key residue for the substrate binding of TMPRSS2, is only carried by non-Finnish European (EUR) populations
- if TMPRSS2 polymorphisms cause gene overexpression, Down Syndrome may be a risk-factor for COVID-19 due to TMPRSS2's localization on chromosome 21.

Population group legend: AFR, African/African-American; AMI, Amish; AMR, Latino/Admixed American; ASJ, Ashkenazi Jewish; EAS, East Asian; FIN, Finnish; EUR, Non-Finnish European; SAS, South Asian; PNA, population not assigned

Nonsynonymous TMPRSS2 Variations by Population

Allelic variants in the ACE2 gene has been observed in different ethinic populations, as well as in case-control studies within ethnic groups. However, these are present in relatively low frequencies. Functional studies are encouraged to characterize the relationship between ACE2 variants and COVID-19 severity, but no causal relationship can be made to date.

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