Loss-of-function mutations in IFNAR2 in COVID-19 severe infection susceptibility

J Glob Antimicrob Resist. 2021 Sep;26:239-240. doi: 10.1016/j.jgar.2021.06.005. Epub 2021 Jul 15.


Recent COVID-19 (coronavirus disease 2019) host genetics studies suggest enrichment of mutations in genes involved in the regulation of type I and type III interferon (IFN) immunity in patients with severe COVID-19 infection. We performed whole-genome sequencing analysis of samples obtained from patients participating in the ongoing ODYSSEY phase 3 study of hospitalised patients with severe COVID-19 infection receiving supplemental oxygen support. We focused on burden testing of categories of rare and common loss-of-function (LOF) variants in all of the IFN pathway genes, specifically with MAF < 0.1% and MAF < 1%. In a model including LOF and missense variants (MAF < 1%), we report a significant signal in both INFAR1 and IFNAR2. We report carriers of rare variants in our COVID-19 cohort, including a stop-gain IFNAR2 (NM_000874:exon9:c.C966A:p.Y322X) amongst carriers of several other IFNAR rare nonsynonymous variants. Furthermore, we report an increased allelic frequency of common IFNAR2 variants in our data, reported also by the COVID-19 Host Genetics Initiative.

Keywords: COVID-19; Therapeutics; Viral genetics; Viral resistance; Whole-genome sequencing.

MeSH terms

  • COVID-19*
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Humans
  • Mutation
  • Receptor, Interferon alpha-beta / genetics
  • SARS-CoV-2


  • IFNAR2 protein, human
  • Receptor, Interferon alpha-beta