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

• DOI: 10.1016/j.jgar.2021.06.005
• Publication Date: 2021-07-15T02:19:01Z
• Authors: Sandra P. Smieszek; Vasilios M. Polym...; Changfu Xiao; Christos M. Polym...; Mihael H. Polymer...
• Keywords: Whole-genome sequencing; 0303 health sciences; SARS-CoV-2; Viral resistance; Short Communication; COVID-19; Therapeutics; Receptor, Interferon alpha-beta; Microbiology; QR1-502; 3. Good health; 03 medical and health sciences; Gene Frequency; Mutation; Humans; Genetic Predisposition to Disease; Viral genetics

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.