Original Article: https://doi.org/10.1038/s41586-020-03065-y
- Severe COVID-19 causes lung inflammation and drives mortality.
- Host genes associated with critical illness may identify targets for treatment.
- A genome-wide association study was conducted in more than 2200 severely ill COVID-19 patients from 208 United Kingdom intensive care units.
- The following are the new genome-wide significant associations that were identified by the researchers:
- Chr19p13.3 dipeptidyl peptidase 9 (DPP9)
- Chr12q24.13 antiviral restriction enzyme activators (OAS1, OAS2, OAS3)
- Chr21q22.1 interferon receptor IFNAR2
- Chr19p13.2 tyrosine kinase 2 (TYK2)
- Dipeptidyl peptidases appear to be involved in the regulation of the activity of their substrates and have been linked to a variety of diseases including type 2 diabetes, obesity and cancer.
- OAS1 and OAS2 encodes protein that activates latent RNase L, which results in viral RNA degradation and the inhibition of viral replication.
- OAS3 is associated with inhibition of cellular protein synthesis and viral infection resistance.
- IFNAR2 encodes a type I membrane protein that forms one of the two chains of a receptor for interferons alpha and beta.
- TYK2 encodes proteins that associates with the cytoplasmic domain of type I and type II cytokine receptors and promulgate cytokine signals by phosphorylating receptor subunits.
- Mutations in IFNAR2 and TYK2 are associated with immunodeficiency.
- Researchers identify potential targets for repurposing of licensed medications.
- The life-threatening disease was linked to low expression of interferon receptor IFNAR2 and high expression of tyrosine kinase 2 TYK2.
- Severe COVID-19 is also associated with high expression of the monocyte/macrophage chemotactic receptor CCR2.
- Data identify genetic signals relating to key host antiviral defense mechanisms, and mediators of inflammatory organ damage in severe COVID-19.
- Both mechanisms may be amenable to targeted treatment with existing drugs.
- Large-scale randomized clinical trials will be necessary before any change to clinical practice.