13.3 Genes Implicated in Severe COVID-19 Infection in Humans

Overview

Susceptibility to severe viral infections was reported to be associated with genetic variants in immune response genes. This article systematically reviewed the genes related to viral susceptibility that were reported in human genetic studies (case-reports and genome wide association studies) to understand the role of host viral interactions and to provide insights into the pathogenesis of severe COVID-19. Approximately 15% of cases are severe and some of them are accompanied by a dysregulated immune system and cytokine storm. There is increasing evidence that severe manifestations of COVID-19 might be attributed to human genetic variants in genes related to immune deficiency and/or inflammasome activation (cytokine storm). Forty genes were found to be associated with viral susceptibility and 21 of them were associated with severe SARSCoV disease and severe COVID-19. Some of those genes were implicated in toll-like receptor pathways, others in C-lectin pathways, and others were related to inflammasome activation (cytokine storm).

A Closer Look at Popular Theories

As researchers work tirelessly to uncover the genetic basis of COVID-19 severity and susceptibility, the following outlines some popular opinions based upon the science, as it stands when this was written. As the science advances, so will our theories and understanding.

• Emily Willingham’s (2020) article, “Genes May Influence COVID-19 Risk, New Studies Hint” at Scientific American, and Jocelyn Kaiser’s (2020) article, “Found: genes that sway the course of the coronavirus” at Science from American Association for the Advancement of Science. speak to early theories concerning Chromosome 3 and ABO blood groups. 
• Another article from from Ann Gibbons (2020) at Science, “Neanderthal gene found in many people may open cells to coronavirus and increase COVID-19 severity” discusses the theory related to Chromosome 2, specifically the DPP4 gene known as the Neanderthal gene found in many people which may open cells to coronavirus and increase COVID-19 severity.
• An article from the National Institutes of Health (NIH, 2020), “Scientists discover genetic and immunologic underpinnings of some cases of severe COVID-19” speaks to a molecular explanation for why more men than women die from COVID-19.
• An article from John Hewitt (2020), Medical Xpress, “Unique susceptibility to unique Sars-CoV-2 variants and vaccines” gives a brief overview of how individuals with different genetic variants in their immune system components often have very different immune responses to SARS-CoV-2, and explains that they also will have different responses to vaccines.

Take a look at the video below by Dr. Alex Hoischen, Radboud University (Bionano Genomics, 2021), where he discusses his published results on genomic variants found in families with severe COVID-19. In two families with severely ill brothers, mutations were found in the Toll-Like Receptor 7 gene (TLR7), which affects the production of interferons, signaling molecules used to control the immune response. Several other studies have since made similar findings in other genes of the TLR family. Dr. Hoischen discussed how individual patients each may carry individually rare variants, that are collectively common and point to important pathways involved in the disease. His interest in the consortium is based on his understanding that larger SVs have a greater chance to be rare and disruptive, and genome-wide studies have lacked so far in their assessment.

The video below, Rare Genetic Variants May Predispose to Severe COVID-19, by Bionano Genomics (2021) on YouTube, discusses the links between genes and incidence of severe COVID-19 infection.

References

Bionano Genomics. (2021, January 22). Rare genetic variants may predispose to severe COVID-19 (video file). YouTube. https://www.youtube.com/watch?v=RaustWij4yg

Elhabyan, A. 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 289(2020), 198163. https://doi.org/10.1016/j.virusres.2020.198163

Gibbons, A. (2020, December 18). Neanderthal gene found in many people may open cells to coronavirus and increase COVID-19 severity. Science. https://www.science.org/content/article/neanderthal-gene-found-many-people-may-open-cells-coronavirus-and-increase-covid-19

Hewitt, J.  (2020, December 30). Unique susceptibility to unique Sars-CoV-2 variants and vaccines. Medical Xpress. https://medicalxpress.com/news/2020-12-unique-susceptibility-sars-cov-variants-vaccines.html

Kaiser, J. (2020, October 13). Found: genes that sway the course of the coronavirus. Science 370(6514), 275-276. https://www.science.org/doi/10.1126/science.370.6514.275

National Institutes of Health (NIH). (2020, September 24). Scientists discover genetic and immunologic underpinnings of some cases of severe COVID-19. U.S. Department of Health and Human Services. https://www.nih.gov/news-events/news-releases/scientists-discover-genetic-immunologic-underpinnings-some-cases-severe-covid-19

Willingham, E. (2020, July 21). Genes may influence COVID-19 risk, new studies hint. Scientific American. https://www.scientificamerican.com/article/genes-may-influence-covid-19-risk-new-studies-hint/