Summary
This genetic study identifies two OAS1 exonic variants (rs10774671-A and rs1131454-A) that reduce OAS1 protein expression through altered splicing and nonsense-mediated decay, and demonstrates their association with increased COVID-19 hospitalization risk in both European and African ancestry cohorts. Functional analyses reveal the mechanistic basis for impaired interferon-lambda-mediated antiviral responses in carriers of the risk haplotype, with implications for understanding why early interferon treatment may mitigate severe COVID-19.
UK applicability
These findings are directly applicable to UK clinical and public health contexts, as the genetic variants occur in both European and African ancestry populations present in the UK. The results support consideration of pharmacogenetic factors in COVID-19 treatment protocols, particularly regarding the use of interferons in high-risk individuals.
Key measures
COVID-19 hospitalization status; OAS1 haplotype frequency; OAS1 protein abundance; SARS-CoV-2 viral clearance; splicing patterns; nonsense-mediated decay activity
Outcomes reported
The study identified genetic variants in OAS1 that regulate protein expression through nonsense-mediated decay and splicing, and associated these with COVID-19 hospitalization risk across European and African ancestry populations. The variants were also associated with reduced SARS-CoV-2 clearance in a pegIFN-λ1 clinical trial.
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