Research Highlights: Genetic Mechanisms in Severe COVID-19

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Electron microscopy photo of the COVID-19 coronavirus. Image Source: https://www.scripps.edu/

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:
  1. Chr19p13.3 dipeptidyl peptidase 9 (DPP9)
  2. Chr12q24.13 antiviral restriction enzyme activators (OAS1, OAS2, OAS3)
  3. Chr21q22.1 interferon receptor IFNAR2
  4. 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.

Source:

https://doi.org/10.1038/s41586-020-03065-y

DPP9 dipeptidyl peptidase 9 [Homo sapiens (human)] – Gene – NCBI (nih.gov)

OAS1 2′-5′-oligoadenylate synthetase 1 [Homo sapiens (human)] – Gene – NCBI (nih.gov)

OAS2 2′-5′-oligoadenylate synthetase 2 [Homo sapiens (human)] – Gene – NCBI (nih.gov)

OAS3 2′-5′-oligoadenylate synthetase 3 [Homo sapiens (human)] – Gene – NCBI (nih.gov)

IFNAR2 interferon alpha and beta receptor subunit 2 [Homo sapiens (human)] – Gene – NCBI (nih.gov)

TYK2 tyrosine kinase 2 [Homo sapiens (human)] – Gene – NCBI (nih.gov)

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