Variant Views

Genetic Mechanisms of Critical Illness in Covid-19

By Malorye Branca on March, 4 2021


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Primary reference:  Pairo-Castineira, et al. Nature. Dec. 11, 2020.

Featured genes:  OAS1, OAS2, OAS3, TYK2, DPP9, IFNAR2.

Since lung inflammation drives mortality in critical illness caused by Covid-19, host genetic variants associated with this illness could be used to find targets for drug repurposing or new candidates for development. This study reports the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study (GWAS) in 2244 critically ill Covid-19 patients from 208 UK intensive care units (ICUs).

This international collaboration identified and replicated novel genome-wide significant associations, on chr12q24.13 (rs10735079, p=1.65 × 10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1OAS2OAS3), on chr19p13.2 (rs2109069, p=2.3 × 10-12) near the gene encoding tyrosine kinase 2 (TYK2), on chr19p13.3 (rs2109069, p=3.98 × 10-12) within the gene encoding dipeptidyl peptidase 9 (DPP9), and on chr21q22.1 (rs2236757, p=4.99 × 10-8) in the interferon receptor gene IFNAR2.

To find targets that could be addressed by already approved medications, the researchers used two approaches.  Using Mendelian randomization, they uncovered evidence of a causal link between life-threatening disease and low expression of IFNAR2 and high expression of TYK2. Further, a transcriptome-wide association in lung tissue revealed that high expression of the monocyte/macrophage chemotactic receptor CCR2 is associated with severe Covid-19.

The researchers say these results identify "robust genetic signals relating to key host antiviral defense mechanisms, and mediators of inflammatory organ damage in Covid-19. Both mechanisms may be amenable to targeted treatment with existing drugs." They also note that large-scale randomized clinical trials will be needed to confirm whether any such findings should lead to changes in clinical practice.


Additional resources:

The ABO blood group locus and a chromosome 3 gene cluster associate with SARS-CoV-2 respiratory failure in an Italian-Spanish genome-wide association analysis. Ellinghaus, D. et al., medRxix, May 31, 2020.  These researchers addressed the question "Why does respiratory failure affect less than 10% of SARS-CoV-2 infected patients?" They report: "the first robust genetic susceptibility loci for the development of respiratory failure in Covid-19. Identified variants may help guide targeted exploration of severe Covid-19 pathophysiology.

ApoE-isoform-dependent SARS-CoV-2 Neurotropism and cellular response.Wang, et al. Cell Stem Cell, Feb. 4, 2021.  ApoE4, which is a strong genetic risk factor for Alzheimer disease, has also been associated with higher risk of severe COVID-19. These authors looked at whether ApoE4 alters COVID-19 susceptibility or severity by testing neurotropism of the virus in hiPSC brain cell models. Their findings "suggest that ApoE4 may play a causal role in COVID-19 severity." 

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