Abstract
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.
【저자키워드】 COVID-19, whole-genome sequencing, Therapeutics, Viral genetics, Viral resistance, 【초록키워드】 coronavirus disease, whole-genome sequencing, Coronavirus disease 2019, Mutation, Immunity, Therapeutics, Sequencing, host genetics, variant, oxygen, COVID-19 infection, Viral genetics, Patient, IFN, Hospitalised patients, IFNAR2, Frequency, Analysis, Viral resistance, Rare variants, type III interferon, Severe COVID-19 Infection, Regulation, carriers, enrichment, type I, IFNAR, categories, COVID-19 Host Genetics Initiative, loss-of-function, nonsynonymous variants, missense variant, carrier, COVID-19 cohort, initiative, phase 3 study, Genes, recent, MAF, supplemental oxygen support, IFN pathway, performed, involved, reported, receiving, hospitalised patient, allelic, category, rare variant, LOF, 【제목키워드】 Severe infection, susceptibility, loss-of-function mutation,