A Critical Look at How Genetics May Be Affecting COVID-19 Disease Severity

By Chloe Teng

The variation in the severity of effects for those infected with SARS-CoV-2 has been a key area of investigation since the initial COVID-19 outbreak in December 2019. Although an estimated 45% of patients present as asymptomatic (Scripps Research Institute, 2020), other COVID-19 cases result in cardiac failure, lung inflammation, and even neurological issues that cause hallucinations. To understand this variation in symptom severity, research has been conducted involving a genome-wide association study (GWAS) of 1980 SARS-CoV-2 infected patients from the Italian and Spanish disease epicentres. It was concluded that two gene loci (one located at chromosome 3p21.31, and another at locus 9q34.2 which is the ABO blood group locus), showed significant association with severe COVID-19 (Ellinghaus et al., 2020).

Firstly, the study identified the rs11385942 insertion-deletion GA or G variant at locus 3p21.31 which consists of six genes (SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6, and XCR1). The risk allele GA of rs11385942 is notably associated with an increased expression of SLC6A20, which is responsible for producing a transporter protein for interaction with the angiotensin-converting enzyme 2 (ACE2) receptor. This is interesting, as ACE2 has been identified as the entry point for SARS-CoV-2 at various organs. Besides that, the binding of the SARS-CoV-2 virus to ACE2 receptors prevents these receptors from regulating angiotensin 2 (ANG2). Consequential enhanced ANG2 levels can lead to increased blood pressure and inflammation, as well as blood vessel and tissue injury. In relation to COVID-19, ANG2 causes cell death in the alveoli due to excessive inflammation. This may be why patients have been observed with the unexpected symptom of blood clots, aside from the more prevalent symptom of pulmonary damage.

For the ABO blood group locus, there appeared to be a reduced risk of severe reactions to infection to individuals of the blood group O, while those with blood group A were at the opposite side of the spectrum – with the highest risk of a severe symptomatic response on infection with SARS-CoV-2 . (Ellinghaus et al., 2020). It was hypothesised that the chance of experiencing blood clotting as a symptom, as shown in critically ill COVID-19 patients, was affected by blood type. Whilst this data coincides with similar studies (Zhao et al.,2020) (Zietz & Tatonetti, 2020) which were conducted using statistical comparison between COVID-19-infected patients and healthy controls from their respective local populations, other research (Latz et al., 2020) failed to replicate such results. The association between ABO blood type and COVID-19 severity must be clearly outlined before it can be used for purposes such as clinical risk profiling; additionally, the underlying pathophysiology causing the differential response to infection must be explicitly understood in order to create effective treatments for infected patients. Previously, research has shown that the antibody against the A blood group, which is found in individuals of blood group O and B, was able to inhibit the SARS-CoV virus (Guillon et al., 2008). The study discovered that the adhesion of viral SARS-CoV S protein with ACE2 receptors in hamster ovary cells failed to occur due to either monoclonal or human anti-A antibodies. Perhaps it is a similar case for SARS-CoV-2 as well. 

In terms of a GWAS analysis, it is necessary to carry out comparisons between a patient group that experienced severe symptoms and one which did not, in order to produce a complete and comprehensive analysis. However, population-based controls were used in this study by Ellinghaus D et al., whereby each individual’s exposure to the SARS-CoV-2 virus becomes difficult to determine. Nevertheless, the results provide a useful foundation for further investigation into the genetic factors that cause the disparity in the severity of COVID-19 disease amongst patients.

As more research is being conducted around the genetic link between the SARS-CoV-2 virus and the severity of COVID-19, it is also worth noting that many genetic studies are often based on populations with European ancestry, thus creating biased data sets where derived conclusions may be inaccurate . This is illustrated in the variation in symptomatic effects between racial groups in the United States; data shows that the African-American and Non-Hispanic population of the United States have a 2.1x higher mortality rate against COVID-19 (CDC, 2020). It is therefore vital that research going forward maintains an expansive data pool, in order to avoid analytical bias and work towards providing greater prospects to those infected with the SARS-CoV-2 virus.

References:

ScienceDaily. 2020. Up to 45 percent of SARS-CoV-2 infections may be asymptomatic. https://www.sciencedaily.com/releases/2020/06/200612172208.htm [Accessed 27th August 2020]

Hackensack Meridian Health. 2020. What are the long-term effects of COVID-19? https://www.hackensackmeridianhealth.org/HealthU/2020/07/29/what-are-the-long-term-effects-of-covid-19/ [Accessed 26th August 2020]

Ellinghaus, D., Degenhardt, F., Bujanda, L., Buti, M., Albillos, A., Invernizzi, P., Fernández, J., Prati, D., Baselli, G., Asselta, R. and Grimsrud, M.M., 2020. Genomewide association study of severe Covid-19 with respiratory failure. New England Journal of Medicine.

Ni, W., Yang, X., Yang, D., Bao, J., Li, R., Xiao, Y., Hou, C., Wang, H., Liu, J., Yang, D. and Xu, Y., 2020. Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19. Critical Care, 24(1), pp.1-10. Available from: doi: 10.1186/s13054-020-03120-0

Sriram K, Insel P, Loomba R. 2020. What is the ACE2 receptor, how is it connected to coronavirus and why it might be key to treating COVID-19? The experts explain. https://theconversation.com/what-is-the-ace2-receptor-how-is-it-connected-to-coronavirus-and-why-might-it-be-key-to-treating-covid-19-the-experts-explain-136928 [ Accessed 27th August 2020]

Zhao, J., Yang, Y., Huang, H.P., Li, D., Gu, D.F., Lu, X.F., Zhang, Z., Liu, L., Liu, T., Liu, Y.K. and He, Y.J., 2020. Relationship between the ABO Blood Group and the COVID-19 Susceptibility. medRxiv. Available from: doi :10.1101/2020.03.11.20031096

Zietz M, Tatonetti N P. Testing the association between blood type and COVID-19 infection, intubation, and death. medRxiv. Available from: doi: 10.1101/2020.04.08.20058073

Latz, C.A., DeCarlo, C., Boitano, L., Png, C.M., Patell, R., Conrad, M.F., Eagleton, M. and Dua, A., 2020. Blood type and outcomes in patients with COVID-19. Annals of Hematology, 99(9), pp.2113-2118. Available from: doi:  10.1007/s00277-020-04169-1

Guillon, P., Clément, M., Sébille, V., Rivain, J.G., Chou, C.F., Ruvoën-Clouet, N. and Le Pendu, J., 2008. Inhibition of the interaction between the SARS-CoV spike protein and its cellular receptor by anti-histo-blood group antibodies. Glycobiology, 18(12), pp.1085-1093. Available from: doi: 10.1093/glycob/cwn093

Olena A. 2020. Two Genetic Regions Linked with Severe COVID-19. https://www.the-scientist.com/news-opinion/two-genetic-regions-linked-with-severe-covid-19-67619. [ Accessed 28th August 2020]

Centers for Disease Control and Prevention. 2020. COVID-19 Hospitalization and Death by Race/Ethnicity. https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-race-ethnicity.html [ Accessed 26th August 2020]

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