학술논문
Genetic regulation of OAS1 nonsense-mediated decay underlies association with COVID-19 hospitalization in patients of European and African ancestries
Document Type
Original Paper
Author
Banday, A. Rouf; Stanifer, Megan L.; Florez-Vargas, Oscar; Onabajo, Olusegun O.; Papenberg, Brenen W.; Zahoor, Muhammad A.; Mirabello, Lisa; Ring, Timothy J.; Lee, Chia-Han; Albert, Paul S.; Andreakos, Evangelos; Arons, Evgeny; Barsh, Greg; Biesecker, Leslie G.; Boyle, David L.; Brahier, Mark S.; Burnett-Hartman, Andrea; Carrington, Mary; Chang, Euijin; Choe, Pyoeng Gyun; Chisholm, Rex L.; Colli, Leandro M.; Dalgard, Clifton L.; Dude, Carolynn M.; Edberg, Jeff; Erdmann, Nathan; Feigelson, Heather S.; Fonseca, Benedito A.; Firestein, Gary S.; Gehring, Adam J.; Guo, Cuncai; Ho, Michelle; Holland, Steven; Hutchinson, Amy A.; Im, Hogune; Irby, Les’Shon; Ison, Michael G.; Joseph, Naima T.; Kim, Hong Bin; Kreitman, Robert J.; Korf, Bruce R.; Lipkin, Steven M.; Mahgoub, Siham M.; Mohammed, Iman; Paschoalini, Guilherme L.; Pacheco, Jennifer A.; Peluso, Michael J.; Rader, Daniel J.; Redden, David T.; Ritchie, Marylyn D.; Rosenblum, Brooke; Ross, M. Elizabeth; Anna, Hanaisa P. Sant; Savage, Sharon A.; Sharma, Sudha; Siouti, Eleni; Smith, Alicia K.; Triantafyllia, Vasiliki; Vargas, Joselin M.; Vargas, Jose D.; Verma, Anurag; Vij, Vibha; Wesemann, Duane R.; Yeager, Meredith; Yu, Xu; Zhang, Yu; Boulant, Steeve; Chanock, Stephen J.; Feld, Jordan J.; Prokunina-Olsson, Ludmila
Source
Nature Genetics. 54(8):1103-1116
Subject
Language
English
ISSN
1061-4036
1546-1718
1546-1718
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.
Genetic and functional studies implicate allele-specific regulation of OAS1 splicing and nonsense-mediated decay in COVID-19 severity. The OAS1 risk haplotype is also associated with reduced SARS-CoV-2 clearance in a clinical trial with pegIFN-λ1.
Genetic and functional studies implicate allele-specific regulation of OAS1 splicing and nonsense-mediated decay in COVID-19 severity. The OAS1 risk haplotype is also associated with reduced SARS-CoV-2 clearance in a clinical trial with pegIFN-λ1.