Genetics of COVID-19: Why Some People Develop Severe Symptoms

Advanced age and comorbidities are known to be high risk factors for COVID-19. Does genetic make-up predispose some people making them more susceptible to severe symptoms? Conversely, does genetic make-up enable some people to have innate immunity making them immune against COVID-19 implying such people may not require vaccines. Identifying people with genetic susceptibility (by way of genome analysis) may provide for a more efficient personalised/precision medicine approach to combat this pandemic and other high burden diseases like cancer.  

COVID-19 is known to disproportionately affect elderly and people with comorbidities however there seems to be another pattern. Apparently, some people are genetically more prone and predisposed to develop severe life-threatening symptoms ¹ as indicated in the reported cases like three brothers in similar age group (who lived separately and were normal health wise) succumbing to COVID-19 ². This small group of people suffer hyperinflammation, clinical deterioration and multiple organ failure caused due to development Cytokine Storm (CS) in which Interleukin-6 (IL-6) is a central mediator. Two common gene polymorphisms that predispose to hyperinflammation are Familial Mediterranean Fever (FMF) and Glucose-6-phosphate Dehydrogenase (G6PD) deficiency which combined with obesity increases the risk further ³.  

A systematic review links susceptibility to genetic variants in immune response genes. Forty genes were found to be associated with susceptibility and 21 of these genes had relation with development of severe symptom ⁴. Another study supports the view that ACE2 gene polymorphism contributes to susceptibility to COVID-19 ⁵. The virus responsible for COVID-19 uses the angiotensin-converting enzyme 2 (ACE2) receptor protein present on the cell surface to enter the cell. Any variation in the ACE2 gene would have strong bearing on predisposition to COVID.  The role of host-genetics in susceptibility to COVID-19 is investigated at the level of structural variants (SV) in a study reported in preprint recently by Sahajpal NS, et al. In this study, the researchers performed genome analysis on 37 severely ill COVID-19 patients. This patient-centric investigation identified 11 large structural variants involving 38 genes with a potential role in development of severe symptoms of COVID-19 ⁶. 

The fast-evolving knowledge base about role of host-genetics in COVID-19 disease progression may indicate appropriate shift of focus towards targeted approach to prevention and treatment of COVID-19. It may be possible to think of precisely targeted interventions to unique genetic-makeup of individuals ⁷. The personalised, precise treatments or interventions however would require genome analysis data at individual level. There may be issue of privacy to deal with however, in the long run, this may prove to be more effective cost wise too.  

Currently, there are some commercial organisations that provide personal services covering basic health predispositions for individuals. However, more organised efforts in the public sector would be needed to build the knowledge base and infrastructure for personalised precision medicine to be a reality. GEN-COVID Multicentre Study ⁸ that aim to derive individual level phenotypic and genotypic data though biobanking and health records to make the data available to COVID-19 researchers worldwide is a step forward in this direction.  

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References:  

1. Kaiser J., 2020. How sick will the coronavirus make you? The answer may be in your genes. Science. Published 27 Mar 2020. DOI: https://doi.org/10.1126/science.abb9192 

2. Yousefzadegan S., and Rezaei N., 2020. Case Report: Death due to COVID-19 in Three Brothers.  The American Journal of Tropical Medicine and Hygiene. Volume 102: Issue 6 Page(s): 1203–1204. Published Online: 10 Apr 2020. DOI: https://doi.org/10.4269/ajtmh.20-0240 

3. Woo Y., Kamarulzaman A., et al 2020. A genetic predisposition for Cytokine Storm in life-threatening COVID-19 infection. OSFPreprints. Created: April 12, 2020. DOI: https://doi.org/10.31219/osf.io/mxsvw    

4. Elhabyan A., Elyaacoub S., et al, 2020. The role of host genetics in susceptibility to severe viral infections in humans and insights into host genetics of severe COVID-19: A systematic review, Virus Research, Volume 289, 2020. Available online 9 September 2020. DOI: https://doi.org/10.1016/j.virusres.2020.198163 

5. Calcagnile M., and  Forgez P., 2020. Molecular docking simulation reveals ACE2 polymorphisms that may increase the affinity of ACE2 with the SARS-CoV-2 Spike protein. Biochimie Volume 180, January 2021, Pages 143-148. Available online 9 November 2020. DOI: https://doi.org/10.1016/j.biochi.2020.11.004   

6. Sahajpal NS, Lai CJ, et al 2021. Host genome analysis of structural variations by Optical Genome Mapping provides clinically valuable insights into genes implicated in critical immune, viral infection, and viral replication pathways in patients with severe COVID-19. Preprint medRxiv. January 8, 2021. DOI: https://doi.org/10.1101/2021.01.05.21249190 

7. Zhou, A., Sabatello, M., Eyal, G. et al. Is precision medicine relevant in the age of COVID-19? Genet Med (2021). Published: 13 January 202. DOI:  https://doi.org/10.1038/s41436-020-01088-4 

8. Daga, S., Fallerini, C., Baldassarri, M. et al. Employing a systematic approach to biobanking and analyzing clinical and genetic data for advancing COVID-19 research. Eur J Hum Genet (2021). Published: 17 January 2021.  https://doi.org/10.1038/s41431-020-00793-7  

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