Abstract
The chr12q24.13 locus encoding OAS1-OAS3 antiviral proteins has been associated with coronavirus disease 2019 (COVID-19) susceptibility. Here, we report genetic, functional and clinical insights into this locus in relation to COVID-19 severity. In our analysis of patients of European (n = 2,249) and African (n = 835) ancestries with hospitalized versus nonhospitalized COVID-19, the risk of hospitalized disease was associated with a common OAS1 haplotype, which was also associated with reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance in a clinical trial with pegIFN-λ1. Bioinformatic analyses and in vitro studies reveal the functional contribution of two associated OAS1 exonic variants comprising the risk haplotype. Derived human-specific alleles rs10774671-A and rs1131454 -A decrease OAS1 protein abundance through allele-specific regulation of splicing and nonsense-mediated decay (NMD). We conclude that decreased OAS1 expression due to a common haplotype contributes to COVID-19 severity. Our results provide insight into molecular mechanisms through which early treatment with interferons could accelerate SARS-CoV-2 clearance and mitigate against severe COVID-19.
【초록키워드】 COVID-19, coronavirus disease, SARS-CoV-2, Coronavirus disease 2019, coronavirus, clinical trial, Hospitalized, severe COVID-19, Antiviral, OAS1, susceptibility, Genetic, variant, interferons, COVID-19 severity, interferon, risk, molecular mechanism, Protein, African, early treatment, Patient, splicing, disease, expression, Haplotype, Analysis, Bioinformatic, acute respiratory syndrome, Regulation, locus, acute respiratory syndrome coronavirus, acute respiratory syndrome coronavirus 2, molecular mechanisms, in vitro study, allele, SARS-CoV-2 clearance, clearance, mitigate, European, decrease, reduced, functional, contribute, analysis, accelerate, exonic, 【제목키워드】 Hospitalization, African, Patient, association, genetic regulation, with COVID-19,