tetano
Editor, Senior Moderator
Nat Genet
. 2022 Jul 14.
doi: 10.1038/s41588-022-01113-z. Online ahead of print.
Genetic regulation of OAS1 nonsense-mediated decay underlies association with COVID-19 hospitalization in patients of European and African ancestries
A Rouf Banday[SUP] #[/SUP][SUP] 1 [/SUP], Megan L Stanifer[SUP] #[/SUP][SUP] 2 3 [/SUP], Oscar Florez-Vargas[SUP] #[/SUP][SUP] 1 [/SUP], Olusegun O Onabajo[SUP] 1 [/SUP], Brenen W Papenberg[SUP] 1 [/SUP], Muhammad A Zahoor[SUP] 4 [/SUP], Lisa Mirabello[SUP] 5 [/SUP], Timothy J Ring[SUP] 1 [/SUP], Chia-Han Lee[SUP] 1 [/SUP], Paul S Albert[SUP] 6 [/SUP], Evangelos Andreakos[SUP] 7 [/SUP], Evgeny Arons[SUP] 8 [/SUP], Greg Barsh[SUP] 9 [/SUP], Leslie G Biesecker[SUP] 10 [/SUP], David L Boyle[SUP] 11 [/SUP], Mark S Brahier[SUP] 12 [/SUP], Andrea Burnett-Hartman[SUP] 13 [/SUP], Mary Carrington[SUP] 14 15 16 [/SUP], Euijin Chang[SUP] 17 [/SUP], Pyoeng Gyun Choe[SUP] 17 [/SUP], Rex L Chisholm[SUP] 18 [/SUP], Leandro M Colli[SUP] 19 [/SUP], Clifton L Dalgard[SUP] 20 [/SUP], Carolynn M Dude[SUP] 21 [/SUP], Jeff Edberg[SUP] 22 [/SUP], Nathan Erdmann[SUP] 23 [/SUP], Heather S Feigelson[SUP] 13 [/SUP], Benedito A Fonseca[SUP] 24 [/SUP], Gary S Firestein[SUP] 11 [/SUP], Adam J Gehring[SUP] 4 25 [/SUP], Cuncai Guo[SUP] 26 [/SUP], Michelle Ho[SUP] 1 [/SUP], Steven Holland[SUP] 27 [/SUP], Amy A Hutchinson[SUP] 28 [/SUP], Hogune Im[SUP] 29 [/SUP], Les'Shon Irby[SUP] 21 [/SUP], Michael G Ison[SUP] 30 [/SUP], Naima T Joseph[SUP] 31 [/SUP], Hong Bin Kim[SUP] 17 32 [/SUP], Robert J Kreitman[SUP] 8 [/SUP], Bruce R Korf[SUP] 33 [/SUP], Steven M Lipkin[SUP] 34 [/SUP], Siham M Mahgoub[SUP] 35 [/SUP], Iman Mohammed[SUP] 36 [/SUP], Guilherme L Paschoalini[SUP] 19 [/SUP], Jennifer A Pacheco[SUP] 18 [/SUP], Michael J Peluso[SUP] 37 [/SUP], Daniel J Rader[SUP] 38 [/SUP], David T Redden[SUP] 39 [/SUP], Marylyn D Ritchie[SUP] 38 [/SUP], Brooke Rosenblum[SUP] 10 [/SUP], M Elizabeth Ross[SUP] 36 [/SUP], Hanaisa P Sant Anna[SUP] 40 [/SUP], Sharon A Savage[SUP] 5 [/SUP], Sudha Sharma[SUP] 41 [/SUP], Eleni Siouti[SUP] 7 [/SUP], Alicia K Smith[SUP] 21 [/SUP], Vasiliki Triantafyllia[SUP] 7 [/SUP], Joselin M Vargas[SUP] 1 [/SUP], Jose D Vargas[SUP] 42 [/SUP], Anurag Verma[SUP] 38 [/SUP], Vibha Vij[SUP] 43 [/SUP], Duane R Wesemann[SUP] 44 [/SUP], Meredith Yeager[SUP] 28 [/SUP], Xu Yu[SUP] 16 [/SUP], Yu Zhang[SUP] 27 [/SUP], Steeve Boulant[SUP] 3 26 45 [/SUP], Stephen J Chanock[SUP] 40 [/SUP], Jordan J Feld[SUP] 4 25 [/SUP], Ludmila Prokunina-Olsson[SUP] 46 [/SUP]
Affiliations
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 Jul 14.
doi: 10.1038/s41588-022-01113-z. Online ahead of print.
Genetic regulation of OAS1 nonsense-mediated decay underlies association with COVID-19 hospitalization in patients of European and African ancestries
A Rouf Banday[SUP] #[/SUP][SUP] 1 [/SUP], Megan L Stanifer[SUP] #[/SUP][SUP] 2 3 [/SUP], Oscar Florez-Vargas[SUP] #[/SUP][SUP] 1 [/SUP], Olusegun O Onabajo[SUP] 1 [/SUP], Brenen W Papenberg[SUP] 1 [/SUP], Muhammad A Zahoor[SUP] 4 [/SUP], Lisa Mirabello[SUP] 5 [/SUP], Timothy J Ring[SUP] 1 [/SUP], Chia-Han Lee[SUP] 1 [/SUP], Paul S Albert[SUP] 6 [/SUP], Evangelos Andreakos[SUP] 7 [/SUP], Evgeny Arons[SUP] 8 [/SUP], Greg Barsh[SUP] 9 [/SUP], Leslie G Biesecker[SUP] 10 [/SUP], David L Boyle[SUP] 11 [/SUP], Mark S Brahier[SUP] 12 [/SUP], Andrea Burnett-Hartman[SUP] 13 [/SUP], Mary Carrington[SUP] 14 15 16 [/SUP], Euijin Chang[SUP] 17 [/SUP], Pyoeng Gyun Choe[SUP] 17 [/SUP], Rex L Chisholm[SUP] 18 [/SUP], Leandro M Colli[SUP] 19 [/SUP], Clifton L Dalgard[SUP] 20 [/SUP], Carolynn M Dude[SUP] 21 [/SUP], Jeff Edberg[SUP] 22 [/SUP], Nathan Erdmann[SUP] 23 [/SUP], Heather S Feigelson[SUP] 13 [/SUP], Benedito A Fonseca[SUP] 24 [/SUP], Gary S Firestein[SUP] 11 [/SUP], Adam J Gehring[SUP] 4 25 [/SUP], Cuncai Guo[SUP] 26 [/SUP], Michelle Ho[SUP] 1 [/SUP], Steven Holland[SUP] 27 [/SUP], Amy A Hutchinson[SUP] 28 [/SUP], Hogune Im[SUP] 29 [/SUP], Les'Shon Irby[SUP] 21 [/SUP], Michael G Ison[SUP] 30 [/SUP], Naima T Joseph[SUP] 31 [/SUP], Hong Bin Kim[SUP] 17 32 [/SUP], Robert J Kreitman[SUP] 8 [/SUP], Bruce R Korf[SUP] 33 [/SUP], Steven M Lipkin[SUP] 34 [/SUP], Siham M Mahgoub[SUP] 35 [/SUP], Iman Mohammed[SUP] 36 [/SUP], Guilherme L Paschoalini[SUP] 19 [/SUP], Jennifer A Pacheco[SUP] 18 [/SUP], Michael J Peluso[SUP] 37 [/SUP], Daniel J Rader[SUP] 38 [/SUP], David T Redden[SUP] 39 [/SUP], Marylyn D Ritchie[SUP] 38 [/SUP], Brooke Rosenblum[SUP] 10 [/SUP], M Elizabeth Ross[SUP] 36 [/SUP], Hanaisa P Sant Anna[SUP] 40 [/SUP], Sharon A Savage[SUP] 5 [/SUP], Sudha Sharma[SUP] 41 [/SUP], Eleni Siouti[SUP] 7 [/SUP], Alicia K Smith[SUP] 21 [/SUP], Vasiliki Triantafyllia[SUP] 7 [/SUP], Joselin M Vargas[SUP] 1 [/SUP], Jose D Vargas[SUP] 42 [/SUP], Anurag Verma[SUP] 38 [/SUP], Vibha Vij[SUP] 43 [/SUP], Duane R Wesemann[SUP] 44 [/SUP], Meredith Yeager[SUP] 28 [/SUP], Xu Yu[SUP] 16 [/SUP], Yu Zhang[SUP] 27 [/SUP], Steeve Boulant[SUP] 3 26 45 [/SUP], Stephen J Chanock[SUP] 40 [/SUP], Jordan J Feld[SUP] 4 25 [/SUP], Ludmila Prokunina-Olsson[SUP] 46 [/SUP]
Affiliations
- PMID: 35835913
- DOI: 10.1038/s41588-022-01113-z
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.