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

Abstract

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