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Variants in ACE2 and TMPRSS2 may explain genetic susceptibility towards COVID-19

The current COVID-19 pandemic has revealed that increased age and the presence of co-existing health conditions, such as cancer, cardiovascular, and respiratory diseases, increase the risk of health difficulties after contracting the virus. However, many young and previously healthy individuals, who do not fit the previous category, experience severe complications and death.

A new study published in BMC Medicine reveals that genetic factors may influence COVID-19 disease susceptibility and attempts to explain current epidemiologic observations.

The genetic factors that may play a role in COVID-19 transmissibility and susceptibility has been largely unknown. A team of researchers led by Feixiong Cheng from the Genomic Medicine Institute examined DNA polymorphisms, the variations in DNA sequences, in the genes, ACE2 and TMPRSS2. A previous study identified ACE2 and TMPRSS2 as key players in guiding SARS-CoV-2 entry into host cells. ACE2 plays a potential role in COVID-19, as SARS-CoV-2 will bind to ACE2 present on epithelial cells of the lungs and gain access into the cells. Thus, upregulation of ACE2 can theoretically increase the risks of COVID-19 infection or development of severe version of the infection. TMPRSS2 is associated with priming viral spike proteins to host cellular receptors. Therefore, examining polymorphisms in these genes is important.

Approximately 81,000 human genomes from three databases were examined. 437 non-synonymous single-nucleotide variants in the protein-coding regions of ACE2 and TMRSS2 were assembled. Many potentially deleterious polymorphisms in both genes were identified, which increases an individual’s risk factor to contract COVID-19.

Several variants are hypothesised to inhibit the interaction between ACE2 and the spike protein of SARS-CoV-1, the virus that caused the 2003 SARS outbreak. The distribution of deleterious variants in ACE2 also differs among nine ethnic populations. For example, several variants are highly present in African/African-American populations and is thought to be involved in the renin-angiotensin system (RAS) function, which regulates blood pressure, fluid balance, and sodium levels. Dysfunction in RAS function can lead to cardiovascular and kidney disorders. Thus, this genetic analysis suggests that variants in ACE2 may play important roles in the susceptibility to COVID-19 and its associated cardiovascular complications. Moreover, the localisation of ACE2 on the X chromosome may explain the observed high risk of infection in males compared to females.

TMPRSS2 is a key gene in prostate cancer and germline deleterious variants in its coding region have been found to occur in different types of cancer. This suggests that the oncogenic roles of the gene may be associated with poor outcomes when individuals are infected with COVID-19. By using single-cell RNA-sequencing analysis in a previous study, researchers found that expression of the gene was highest in ciliated cells and type I alveolar epithelial cells, with increasing levels in aging humans and mice. This may help explain the relative protection harboured by the younger population from COVID-19 infections.

The differences of genetic variants in different populations offer a guide to highly personalised treatment of COVID-19, as different variants mean differences in biological mechanisms and interaction with available drugs. However, this study used genomic databases from the general population. Thus, a systematic investigation has to be conducted in patients who have been infected with the virus to determine if polymorphisms in ACE2 and TMPRSS2 truly play a role in the increased risk of infection.

Image credit: Medical vector created by kjpargeter –