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.

Michigan State University

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

Hou, Y., Zhao, J., Martin, W., Kallianpur, A., Chung, M. K., Jehi, L., ... & Cheng, F. (2020). New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis. BMC Medicine, 18(1), 1-8.
https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-020-01673-z

New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis

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

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.  

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

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.

Learn Before

Related