Among a large sample of patients with coronavirus 2019 (COVID-19), researchers found that genetic variation – caused by amino acid substitution from valine to methionine – is associated with a lower chance of malignancy. disease.
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, can have a multifaceted effect on humans. Some people have no symptoms; some have a mild fever, sore throat, among other symptoms; but in others, the disease is more severe and often fatal.
In addition to age, sex, and other diseases, genetics has also emerged as another test of the depth of COVID-19. Genetic differences involved in the regulation of interferon immunity associated with COVID-19 are severe. Genome-wide association studies (GWAS) have identified several genetic groups associated with hard COVID-19.
The protein, transmembrane serine-type 2 protease (TMPRSS2), plays an important role in the entry of SARS-CoV-2 into host cells. It is expressed in the lungs, colon, stomach, salivary glands, and other tissues. In the lungs, it is expressed in combination with the angiotensin converting enzyme 2 (ACE2), a receptor to which SARS-CoV-2 binds.
Studies have shown that TMPRSS2 inhibition prevents SARS-CoV-2 infection in vitro. Mice are infected with SARS-CoV-2, when treated with the serine protease inhibitor camostat mesylate, with a high survival rate.
Therefore, a team of researchers thought that naturally occurring changes in the TMPRSS2 gene could affect the structure of the TMPRSS2 protein and could alter the severity of SARS-CoV infection. -2.
Analyzing changes in the TMPRSS2 gene
The team analyzed 378 TMPRSS2 genetic modifications in the GnomAD database for population genetic modifications and reported their findings in a paper published in the medRxiv * preprint server. They created a 3D structural model of the protein, identified the different bonds that stabilize its structure and how that affects naturally occurring byproducts in the amino acids.
Of the 137 changes expected to affect the structure and / or function of TMPRSS2, 136 are rare in the human population. The remaining variant, rs12329760, causes methionine to be replaced by the evaporator-retained valve.
The team analyzed the association between this variant of the TMPRSS2 gene and hard COVID-19 using 2,244 critically ill patients and compared them with 11,220 ancestor-matched people who tested negative for SARS-CoV-2.
They found that the small T allele of rs12329760 was strongly associated with a protective effect against COVID-19 in humans of European ancestry, and those of East Asian ancestry to a lesser extent. A similar effect was observed in South Asian and African individuals, but the result was not statistically significant, possibly due to small sample sizes. The protective effect was confirmed by a larger GWAS meta-analysis.
Although the results confirm the protective effect of the mutation, more studies on asymptomatic or patients with mild symptoms are needed to understand its effect against mild viral infections.
Incidence frequency rs12329760 varies among the population, with the higher frequency seen in East Asian and Finnish people than South Asian or European. The lowest frequency is in Latino and Jewish-Ashkenazi populations. Further studies of populations outside Europe are needed to understand the impact of the severity of SARS-CoV-2 infection on different groups.
Variation in TMPRSS2 can have a protective effect
The authors write:
While the differences in the proportion of SARS-CoV-2 patients who develop severe COVID-19 across different population populations are more likely to be explained by social behavior, public health measures to prevent outbreaks, exposure to other viruses and immunological factors, human genetic differentiation. different numbers can add a little to the differences that have been seen. ”
The authors also tested the effect of the TMPRSS2 V160M on its structure and function in 293T cells expressing ACE2. The wild-type TMPRSS2 is present in half the total length and half in the pure protein structure. However, the V160M variant had a higher proportion of the full-length protein compared to the full-length version, indicating that the variant could inhibit autocleavage of the protein.
Thus, the results indicate that the V160M differential leads to a less active TMPRSS2, which is less able to cleanse SARS-CoV-2 spike proteins and help with infection. Thus, TMPRSS2 may have additional functions in addition to its role in the activation of the spike protein. Like other soluble serine proteases, the soluble TMPRSS2 may play a role in stimulating inflammation in various tissues.
* Important message
medRxiv publish preliminary scientific reports that are not peer-reviewed and, therefore, should not be seen as final, guiding health-related clinical practice / behavior, or be treated as information established.