1. Genetic regulation of OAS1 nonsense-mediated decay underlies association with COVID-19 hospitalization in patients of European and African ancestries.
- Author
-
Banday AR, Stanifer ML, Florez-Vargas O, Onabajo OO, Papenberg BW, Zahoor MA, Mirabello L, Ring TJ, Lee CH, Albert PS, Andreakos E, Arons E, Barsh G, Biesecker LG, Boyle DL, Brahier MS, Burnett-Hartman A, Carrington M, Chang E, Choe PG, Chisholm RL, Colli LM, Dalgard CL, Dude CM, Edberg J, Erdmann N, Feigelson HS, Fonseca BA, Firestein GS, Gehring AJ, Guo C, Ho M, Holland S, Hutchinson AA, Im H, Irby L, Ison MG, Joseph NT, Kim HB, Kreitman RJ, Korf BR, Lipkin SM, Mahgoub SM, Mohammed I, Paschoalini GL, Pacheco JA, Peluso MJ, Rader DJ, Redden DT, Ritchie MD, Rosenblum B, Ross ME, Anna HPS, Savage SA, Sharma S, Siouti E, Smith AK, Triantafyllia V, Vargas JM, Vargas JD, Verma A, Vij V, Wesemann DR, Yeager M, Yu X, Zhang Y, Boulant S, Chanock SJ, Feld JJ, and Prokunina-Olsson L
- Subjects
- 2',5'-Oligoadenylate Synthetase genetics, 2',5'-Oligoadenylate Synthetase metabolism, Alleles, Hospitalization, Humans, SARS-CoV-2 genetics, COVID-19 genetics
- 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., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
- Published
- 2022
- Full Text
- View/download PDF