Apply

Genetics and COVID-19

 

Why do people’s immune systems and bodies respond differently to the novel coronavirus? Even with the same viral dose, people experience differences in severity and symptoms. Scientists are beginning to unravel the complex genetic risks that mediate COVID-19 severity. This research gives us clues as to why some people have symptoms that persist months after infection. Can any of these findings inform the way we treat patients or assess disease risk? You might wonder if any of this information is actionable. While there’s been immense research progress in the past few months, the science presently still leaves many mysteries unsolved. 

 

The Impact of Host Genetics

In any human disease, the genetics of the host plays an important role. A microbe itself could be benign or pathogenic. It is our genes code for the machinery that responds to it. Variations in our genes associate with complications to many diseases. By way of example, the CCR5-delta 32 gene variant associates with HIV-1 infection in people with European ancestry. With respect to COVID-19, we are just beginning to understand how our genetics associate with symptom profile and immunological response to infection. Below, I describe many candidate genes and variants that have been shown to be associated with COVID-19 severity. These studies focus on the genetic variants that put people at risk for severe complications. However, there is less data assessing differences within more moderate or minor levels of COVID-19 severity, long COVID-19 or asymptomatic cases.

 

Viral Receptor Genes

 

The SARS-CoV-2 virus must attach itself to a receptor on the surface of our cells. The ACE2 gene encodes this receptor. It allows the SARS-CoV-2 virus to infect our body, causing COVID-19. This gene is also involved regulating blood pressure and thus implicated in hypertension. The TMPRSS2 gene is also required for SARS-CoV-2 to enter into our cells. Would different variants of these genes confer resistance or susceptibility to COVID-19?

 

The Lifelines population cohort of 36,339 volunteers examined this possibility, albeit indirectly. They investigated 178 different phenotypes as well as 1,273 genomic variants of ACE2 and TMPRSS2. By sampling the blood serum of volunteers, they could assess the amount of immune-signalling proteins and cells in the subjects’ blood.These volunteers had not contracted COVID-19, so. Tthe study focused on finding links to cardiovascular or inflammatory symptoms in general that might provide insight into the degree of inflammatory response a person experienced in response to COVID-19 infection. 

 

A change in one nucleotide near the TMPRSS2 gene was associated with the number of platelets in the blood. Meanwhile, people with specific variants of the ACE2 gene were more likely to need to take hypertension and anti-inflammatory medication. However, these interactions did not surpass the threshold of significance. They do, however, suggest a putative mechanism for how specific variants of these genes may lead to more severe forms of COVID-19.

 

Despite that promise,, another study found these gene variants were not, in fact, associated with disease severity. That does not mean that they have no role in COVID-19:  It turns out that TMPRSS2 variants may influence the risk of getting COVID-19 infection even if they do not affect severity. The specific influence of these two variants is still under further investigation.

 

 

Inflammatory and Immune System Response Genes

 

Another promising avenue for exploring genetic risk is with respect to immune system gene expression. Cytokines are small proteins that communicate with cells of the immune system as part of an inflammatory response to an invader. The number of different cytokines in a patient’s serum is associated with disease severity. Many biologic therapeutics blocked a specific cytokine, interleukin-6, with varied clinical efficacy. Would genetic variants of the interleukin-6 receptor then mediate disease severity? 

 

Researchers assessed seven different genetic polymorphisms in the interleukin-6 receptor as potential putative variants associated with COVID-19 symptom severity. However, only one of these variants, the rs2228145, is well characterized. People with one or two copies of a particular version of this variant show fewer IL-6 receptors on the surface of their cells. Thus, there may be fewer opportunities for initiating an immune signalling cascade. In this way, the variant may contribute to a reduced risk of COVID-19 hospitalization. This is but another hypothesis that needs experimental evaluation, however. 

 

People with specific blood types are at a higher risk of COVID-19. The mechanism behind this effect likely involves the immune system. A large study found that blood type A was associated with respiratory failure. Meanwhile, blood type O showed protective effects against severe forms of COVID-19. This study also identified another location on the genome, 3p21.31, associated with COVID-19 risk (this area is located near the genes: SLC6A20, LZTFL1, CCR9, FYC01, CXCR6, XCR1). Meanwhile, in July 2020, researchers found that the IFTN3 variant rs12252-C was associated with disease severity. This gene encodes a protein already associated with influenza severity. The genotypes of 80 patients (56 with mild disease and 24 with severe disease) were compared to their disease severity. Patients who had two copies of the C variant of this gene showed a higher risk for severe disease. 

 

Elaborating on this finding, variants of the IFITM3 gene are associated with case fatality rates among multiple ethnic groups. Bolstering this association was a recent study that found the variant was more frequently found in hospitalized patients than in controls. The frequency of this specific allele is much lower in white Europeans than in Asian people. This variant could explain differences in severity and fatality rates across countries– namely, that the fatality rate appears to be lower in many Asian countries. 

 

Untargeted Approaches to Identify Genetic Risks

 

Do certain genetic variants increase susceptibility to COVID-19 mortality? Using data from 1778 infections (445 deaths) in the UK, researchers looked for clues. They found eight different ‘super variants’ (that is combinations of alleles that co-occur in a given genome) linked with COVID-19 mortality. Two of these super variants are related to cilia dysfunction (found in the genes DNAH7 and CLUAP1). Cilia are small hairs found on the surface of lung cells that clear our mucus (among other functions). Mucus captures potential pathogens, whereby the cilia transport them out of the airways. 

 

Other super variants implicated genes involved in heart disease (DES and SPEG), blood clotting diseases (STXBP5), mitochondrial dysfunction (TOMM7) and the immune system (WSB1). Another risk factor for severe COVID-19 disease is inherited from Neanderthals. Among 3,199 hospitalized patients, those with a specific genomic segment that resulted from archaic interbreeding with Neanderthals were at an increased risk. This segment is found in roughly half of all people in South Asia and approximately one in six people in Europe. Scientists are not sure how this specific segment contributes to disease risk. Other Neanderthal genetic variants were protective, however. 

 

A UK genome-wide association study identified yet more genes associated COVID-19 severity. Low expression of the IFNAR2 gene was associated with critical disease in the cohort. This receptor is found on the surface of cells, allowing them to respond to viral infections. Additionally, high expression of TYK2 was associated with a life-threatening manifestation of the disease. Finally, CCR2 expression was also linked to severe disease. This is a signalling protein that helps direct immune cells towards different targets. 

 

What We Still Don’t Know

In less than two years, we have learned much about COVID-19 and host immune response. Studying host susceptibility can inform appropriate public health actions. Below, I summarize some of the current findings on genetic variants that influence COVID-19 severity. 

  • ACE2 and TMPRSS2: These genes allow the virus to enter the body. However, the evidence is inconsistent.
  • Blood type A confers risk to severe COVID-19, while blood group O is protective
  • The IFTN3 variant rs12252-C associated with disease severity
  • Untargeted approaches reveal even more connections with immune system genes – such as TYK2, CCR2, and INFAR2

The frequency of such variation across different populations can help explain differences in infection rates and mortality rates. There are many unanswered questions, however. Specifically, the genetic influences discovered so far explain only a small fraction of variation in COVID-19 severity.  But pathogen-host interaction is complex; and it may be the case that certain mutations in the virus itself change the landscape in terms of what host genetics influence disease susceptibility or severity.  Natural selection works rapidly for a virus in a pandemic situation such as this one as the virus adapts to the immunity achieved by hosts through exposure or vaccination.  Thus, it is important that we keep studying not only the genetics of the virus but also host genetics as we continue to battle this pathogen over the long term.   

 

Sources:

 

Yong, Ed. Long-Haulers Are Redefining COVID-19. The Atlantic. March 2020. Online link: https://www.theatlantic.com/health/archive/2020/08/long-haulers-covid-19-recognition-support-groups-symptoms/615382/

 

Murray, M.F., Kenny, E.E., Ritchie, M.D. et al. COVID-19 outcomes and the human genome. Genet Med 22, 1175–1177 (2020). https://doi.org/10.1038/s41436-020-0832-3

 

Ni, Jun, Dan Wang, and Sheng Wang. “The CCR5-Delta32 genetic polymorphism and HIV-1 infection susceptibility: a meta-analysis.” Open Medicine 13.1 (2018): 467-474.

 

Shang, J., Ye, G., Shi, K. et al. Structural basis of receptor recognition by SARS-CoV-2. Nature 581, 221–224 (2020). https://doi.org/10.1038/s41586-020-2179-y

 

Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., … & Pöhlmann, S. (2020). SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell, 181(2), 271-280.

 

Lopera Maya, E. A., van der Graaf, A., Lanting, P., van der Geest, M., Fu, J., Swertz, M., Franke, L., Wijmenga, C., Deelen, P., Zhernakova, A., Sanna, S., & Lifelines Cohort Study (2020). Lack of Association Between Genetic Variants at ACE2 and TMPRSS2 Genes Involved in SARS-CoV-2 Infection and Human Quantitative Phenotypes. Frontiers in genetics, 11, 613. https://doi.org/10.3389/fgene.2020.00613

 

Asselta, R., Paraboschi, E. M., Mantovani, A., & Duga, S. (2020). ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy. Aging, 12(11), 10087–10098. https://doi.org/10.18632/aging.103415

 

Irham, L. M., Chou, W. H., Calkins, M. J., Adikusuma, W., Hsieh, S. L., & Chang, W. C. (2020). Genetic variants that influence SARS-CoV-2 receptor TMPRSS2 expression among population cohorts from multiple continents. Biochemical and biophysical research communications, 529(2), 263–269. https://doi.org/10.1016/j.bbrc.2020.05.179

 

Rubin, E. J., Longo, D. L., & Baden, L. R. (2021). Interleukin-6 Receptor Inhibition in Covid-19—Cooling the Inflammatory Soup.

 

Bovijn, J., Lindgren, C. M., & Holmes, M. V. (2020). Genetic variants mimicking therapeutic inhibition of IL-6 receptor signaling and risk of COVID-19. The Lancet Rheumatology, 2(11), e658-e659.

 

Garbers, C., Monhasery, N., Aparicio-Siegmund, S., Lokau, J., Baran, P., Nowell, M. A., … & Scheller, J. (2014). The interleukin-6 receptor Asp358Ala single nucleotide polymorphism rs2228145 confers increased proteolytic conversion rates by ADAM proteases. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1842(9), 1485-1494.

 

Severe Covid-19 GWAS Group. (2020). Genomewide association study of severe Covid-19 with respiratory failure. New England Journal of Medicine, 383(16), 1522-1534.

 

Valenti, L., Griffini, S., Lamorte, G., Grovetti, E., Uceda Renteria, S. C., Malvestiti, F., Scudeller, L., Bandera, A., Peyvandi, F., Prati, D., Meroni, P., & Cugno, M. (2021). Chromosome 3 cluster rs11385942 variant links complement activation with severe COVID-19. Journal of autoimmunity, 117, 102595. https://doi.org/10.1016/j.jaut.2021.102595

 

Zhang, Y., Qin, L., Zhao, Y., Zhang, P., Xu, B., Li, K., … & Jin, R. (2020). Interferon-induced transmembrane protein 3 genetic variant rs12252-C associated with disease severity in coronavirus disease 2019. The Journal of infectious diseases, 222(1), 34-37.

 

Zhang, Y. H., Zhao, Y., Li, N., Peng, Y. C., Giannoulatou, E., Jin, R. H., … & Dong, T. (2013). Interferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with severe influenza in Chinese individuals. Nature communications, 4(1), 1-6.

 

Kim, Yong-Chan, and Byung-Hoon Jeong. “Strong Correlation between the Case Fatality Rate of COVID-19 and the rs6598045 Single Nucleotide Polymorphism (SNP) of the Interferon-Induced Transmembrane Protein 3 (IFITM3) Gene at the Population-Level.” Genes vol. 12,1 42. 30 Dec. 2020, doi:10.3390/genes12010042

 

Gómez, J., Albaiceta, G. M., Cuesta-Llavona, E., García-Clemente, M., López-Larrea, C., Amado-Rodríguez, L., … & Coto, E. (2021). The Interferon-induced transmembrane protein 3 gene (IFITM3) rs12252 C variant is associated with COVID-19. Cytokine, 137, 155354.

 

Hu, J., Li, C., Wang, S., Li, T., & Zhang, H. (2021). Genetic variants are identified to increase risk of COVID-19 related mortality from UK Biobank data. Human genomics, 15(1), 1-10.

 

Tilley, A. E., Walters, M. S., Shaykhiev, R., & Crystal, R. G. (2015). Cilia dysfunction in lung disease. Annual review of physiology, 77, 379-406.

 

Zeberg, H., Pääbo, S. The major genetic risk factor for severe COVID-19 is inherited from Neanderthals. Nature 587, 610–612 (2020). https://doi.org/10.1038/s41586-020-2818-3

 

Pairo-Castineira, E., Clohisey, S., Klaric, L. et al. Genetic mechanisms of critical illness in COVID-19. Nature 591, 92–98 (2021). https://doi.org/10.1038/s41586-020-03065-y