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Genetic Variants Associated with Severe Covid-19

Written by Vered Smith, Science Writer 

Researchers have published a paper revealing genetic variants associated with the development of life-threatening Covid-19. 

Using GWAS analysis they found 16 independent variants, many within genes involved in the immune response, associated with increased susceptibility to critical Covid-19. Transcriptome wide association study (TWAS) analysis and mendelian randomisation further implicated several genes. These could be druggable targets, allowing the development of new treatment options. 

This study was carried out by researchers from the GenOMICC (Genetics of Mortality in Critical Care) study, an open-source international programme that researches life-threatening diseases. In this study, researchers performed whole genome sequencing of 7,491 critically-ill Covid-19 cases and 48,400 controls, and then compared them to determine mechanisms of critical disease development.  

GWAS Results – Variants Involved in Interferon Signalling and Immune Cell Development 

Five of the 16 significantly associated variants play a direct role in interferon signalling. These include a substitution in IFNA10, and reduced expression of a subunit of its receptor IFNAR2. A variant of a kinase TYK2 associated with its increased expression was identified, as well as a missense variant in IL10RB, a receptor for Type III interferons. The fifth variant was in PLSCR1 (phospholipid scramblase 1), a protein involved in the antiviral effect of interferon, and control of RNA virus replication. This indicated that reduced interferon signalling may increase susceptibility to critical Covid-19. 

Several variants of significance were on genes involved in lymphopoiesis (the development of white blood cells) and differentiation of myeloid cells. Firstly, BCL11A is a gene crucial in B cell and T cell lymphopoiesis, and is involved in promoting plasmacytoid dendritic cell differentiation. TAC4 regulates B cell lymphopoiesis and antibody production, and promotes dendritic cell survival. CSF2 encodes for granulocyte-macrophage colony stimulating factor (GMCSF), and although here a variant of uncertain significance was found, previous data show that GMCSF is upregulated in critical Covid-19.  

TWAS and Mendelian Randomisation Provide Further Potential Targets 

TWAS (as well as fine mapping and colocalisation) provided evidence that an association with rs41264915 may be mediated through increased expression of MUC1. This highlighted the potential role of targeting mucins to prevent the development of critical Covid-19.  

Through Mendelian randomisation, the researchers discovered the first genetic evidence for coagulation factors (F8) and platelet activation (PDGFRL) playing a role in causing critical Covid-19. They also identified adhesion molecules that recruit inflammatory cells to sites of inflammation, including E-selectin (SELE), intercellular adhesion molecule 5 (ICAM5), and dendritic cell-specific intercellular adhesion molecule-3-Grabbing non-integrin (DC-SIGN, CD209). Each of these could be individual therapeutic targets.  

Impact of the Study  

The genetic variants associated with critical Covid-19 reveal new biological mechanisms triggered by the virus. They also provide a starting point for the development of new drugs. As Professor Kenneth Baillie, the chief investigator of the study, and a Consultant in Critical Care Medicine at University of Edinburgh said, “This gives us a deep understanding of the process of disease and is a big step forward in finding more effective treatments.” Translating this research into the clinic is the next challenge, and further studies to enable this are a priority.

Image Credit: Canva

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covid-19 / Genetic Variants