Genetic regulation of OAS1 nonsense-mediated decay underlies association with COVID-19 hospitalization in patients of European and African ancestries.
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
received:
06
07
2021
accepted:
26
05
2022
pubmed:
15
7
2022
medline:
10
8
2022
entrez:
14
7
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35835913
doi: 10.1038/s41588-022-01113-z
pii: 10.1038/s41588-022-01113-z
pmc: PMC9355882
doi:
Substances chimiques
OAS1 protein, human
EC 2.7.7.-
2',5'-Oligoadenylate Synthetase
EC 2.7.7.84
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1103-1116Subventions
Organisme : NIAID NIH HHS
ID : K23 AI157875
Pays : United States
Organisme : NIAID NIH HHS
ID : L30 AI147159
Pays : United States
Organisme : NIGMS NIH HHS
ID : SC1 GM093999
Pays : United States
Commentaires et corrections
Type : UpdateOf
Informations de copyright
© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
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