What causes the variation in susceptibility to COVID-19?

By Linya Thng

Mortality and mortality rates are increasing drastically with age and current health conditions. Through attempts to explain the inconsistent variation in susceptibility of Coronavirus Disease 2019 (COVID-19), a new set of 68 genes (associated with high risk of developing severe COVID-19) reveal important insights. COVID-19, caused by the severely acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) is oddly selective. What is the mechanism behind this mystery? It is commonly known that the severity of SARS-CoV-2 is much greater than other viruses such as the influenza virus. On the 29th of January 2020, the WHO announced a fatality rate of 2% (lower than previous estimates of 3%) (Moscola et al., 2020). A large-scale study was recently conducted by the American Medical Association in the state of New York, USA. The study involved performing antibody tests on over 15,000 grocery stores and community centres over a two-week period to achieve a baseline infection rate, concluding that 19.9% of citizens in the state had COVID-19 antibodies. This produced an infection mortality rate of 1.4%. We can conclude two primary facts from the recent New York state study. Upon concluding the study on May 1st, 2020, there were 166,883 confirmed cases of the virus, yet the study suggests over 1,671,351 have COVID-19 antibodies and have hence contracted the virus, indicating less than 10% of cases were confirmed. This insinuates that a large proportion of the cases were asymptomatic – the disease does not produce the common symptoms of coughs and fever. What causes this selectiveness?

In addition, and perhaps more significantly, the study showed the ability to contract SARS-CoV-2 varies largely based on ethnicity. Approximately 7% of white-tested people had the virus antibodies, much lower than other ethnicities; 11.1% in Asians, 17.4% in African American and a staggering 25.4% in the Hispanics Latino population. The logical conclusion is that the genetics of an individual seems to affect an individual’s ability to contract the disease as well as the severity of the reaction. A previous study by the National Health Commission (NHC) of China found by analysis of the death cases that the two greatest factors affecting the severity of COVID-19 was age and underlying diseases. As early as February, the NHC reported that over 80% of death cases due to COVID-19 were elderly – over the age 60. Additionally, over 75% of death cases had cardiovascular diseases, diabetes, and in some cases, tumour.

The investigation into the genetic susceptibility to COVID-19 involves examining DNA polymorphisms of the two key host factors of SARS-CoV-2 from ~ 81,000 human genomes across 8 populations (Hou et al., 2020). SARS-CoV-2 is dependent on the host cell factors angiotensin-converting enzyme 2 (ACE2) and the host transmembrane-protease serine TMPRSS2. With the assistance of single-cell RNA sequencing, the expression of ACE2 and TMPRSS2 is suggested to dictate SARS-CoV-2 tissue tropism. ACE2 is a receptor that can be found in every human being, with particularly high abundance in the lung tissue, but the quantity varies in people and different types of tissues and cells. Promoting the entry into cells, ACE2 is encoded on the X-chromosome and is responsible for catalysing the conversion of angiotensin II to angiotensin, which serves as a vasodilator which plays a vital role in the cardiovascular system. TMPRSS2 is a key gene in prostate cancer and its enzyme activity aid the spread of coronavirus and pathogenesis in the infected host. TMPRSS2 gene encodes a transmembrane protease serine-2, an enzyme from the serine protease family known for its involvement in pathological processes such as viral pathogenesis. SARS-CoV-2 uses the ACE2 receptor for cell entry, in synergy with the host’s serine-2 enzyme. Specifically, the viral S glycoprotein is cleaved by transmembrane protease serine-2, thus facilitating viral activation and representing a vital host factor for SARS-CoV-2 pathogenicity. ACE2 polymorphisms is suggested to be associated with cardiovascular and pulmonary conditions through the alteration of ACE2 is more localised to the X chromosome which may explain why there is a larger proportion of male infection fatality rate than female and is much more likely to undergo angiotensinogen-ACE2 interactions in the African/African American population.

What does this mean for the future of the pandemic? Understanding the genetic determinants of COVID-19 severity is vital in the fight against the virus. This understanding can be improved by better analysis of data from clinical trials of larger populations of various demographics than are currently being tested of DNA polymorphisms in ACE2 and TMPRSS2 to achieve more accurate statistics of COVID-19 susceptibility, as well as better resolutions of the protein structure of the TMPRSS2 protein which is currently not yet available. This combination of statistics and a better comprehension of genetic and cellular mechanisms will enhance personalized treatment strategies for COVID-19 and precise medicine available; and provides an insight to governments and health associations of who to better protect. Finally, it will make a seemingly unpredictable and incalculable nature of the pandemic more transparent and unambiguous.


Hou, Y., Zhao, J., Martin, W., Kallianpur, A., Chung, M.K., Jehi, L., Sharifi, N., Erzurum, S., Eng, C. and Cheng, F., 2020. New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis. BMC medicine18(1). 18(1),. https://doi.org/10.1186/s12916-020-01673-z

Moscola, J., Sembajwe, G., Jarrett, M., Farber, B., Chang, T., McGinn, T. and Davidson, K.W., Prevalence of SARS-CoV-2 Antibodies in Health Care Personnel in the New York City Area. JAMA. Published online August 06 2020.  doi:10.1001/jama.2020.14765

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