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Genetic regulation of OAS1 nonsense-mediated decay underlies association with COVID-19 hospitalization in patients of European and African ancestries.

A Rouf BandayMegan L StaniferOscar Florez-VargasOlusegun O OnabajoBrenen W PapenbergMuhammad Atif ZahoorLisa MirabelloTimothy J RingChia-Han LeePaul S AlbertEvangelos AndreakosEvgeny AronsGregory S BarshBarbara B BieseckerDavid L BoyleMark S BrahierAndrea Burnett-HartmanMary N CarringtonEuijin ChangPyeong Gyun ChoeRex L ChisholmLeandro Machado ColliCliffton L DalgardCarolynn M DudeJeff EdbergNathan ErdmannHeather Spencer FeigelsonBenedito Antônio Lopes da FonsecaGary S FiresteinAdam J GehringCuncai GuoMichelle HoSteven HollandAmy A HutchinsonHogune ImLes'Shon IrbyMichael G IsonNaima T JosephHong Bin KimRobert J KreitmanBruce R KorfSteven M LipkinSiham M MahgoubIman MohammedGuilherme L PaschoaliniJennifer Allen PachecoMichael J PelusoDaniel James RaderDavid T ReddenMarylyn DeRiggi RitchieBrooke RosenblumMargaret Elizabeth RossHanaisa P Sant AnnaSharon A SavageSudha SharmaEleni SioutiAlicia K SmithVasiliki TriantafylliaJoselin M VargasJose D VargasAnurag VermaVibha VijDuane R WesemannMeredith YeagerXu YuYu ZhangSteeve BoulantStephen J ChanockJordan J FeldLudmila Prokunina-Olsson
Published in: Nature genetics (2022)
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.
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