Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19.
COVID-19
Immunity
Rare variants
Type I interferon
Journal
Genome medicine
ISSN: 1756-994X
Titre abrégé: Genome Med
Pays: England
ID NLM: 101475844
Informations de publication
Date de publication:
05 04 2023
05 04 2023
Historique:
received:
15
09
2022
accepted:
10
03
2023
medline:
7
4
2023
entrez:
5
4
2023
pubmed:
6
4
2023
Statut:
epublish
Résumé
We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P = 1.1 × 10 Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.
Sections du résumé
BACKGROUND
We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases.
METHODS
We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.
RESULTS
No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P = 1.1 × 10
CONCLUSIONS
Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.
Identifiants
pubmed: 37020259
doi: 10.1186/s13073-023-01173-8
pii: 10.1186/s13073-023-01173-8
pmc: PMC10074346
doi:
Substances chimiques
Toll-Like Receptor 3
0
Toll-Like Receptor 7
0
Interferon Type I
0
Autoantibodies
0
Banques de données
ClinicalTrials.gov
['NCT04262921', 'NCT04259892', 'NCT04352348']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
22Subventions
Organisme : NHGRI NIH HHS
ID : UM1 HG006504
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI088364
Pays : United States
Organisme : NIH HHS
ID : S10 OD018521
Pays : United States
Organisme : NCRR NIH HHS
ID : UL1 RR024143
Pays : United States
Organisme : Medical Research Council
ID : MR/S032304/1
Pays : United Kingdom
Organisme : NIAID NIH HHS
ID : R01 AI163029
Pays : United States
Organisme : NHGRI NIH HHS
ID : U24 HG008956
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001866
Pays : United States
Investigateurs
Laurent Abel
(L)
Saleh Al-Muhsen
(S)
Fahd Al-Mulla
(F)
Mark S Anderson
(MS)
Evangelos Andreakos
(E)
Andrés A Arias
(AA)
Hagit Baris Feldman
(HB)
Alexandre Belot
(A)
Catherine M Biggs
(CM)
Dusan Bogunovic
(D)
Anastasiia Bondarenko
(A)
Ahmed A Bousfiha
(AA)
Petter Brodin
(P)
Yenan Bryceson
(Y)
Carlos D Bustamante
(CD)
Samya Chakravorty
(S)
John Christodoulou
(J)
Murkesh Desai
(M)
Beth A Drolet
(BA)
Jamila El Baghdadi
(JE)
Sara Espinosa-Padilla
(S)
José Luis Franco
(JL)
Antoine Froidure
(A)
David Hagin
(D)
Sarah E Henrickson
(SE)
Elena W Y Hsieh
(EWY)
Eystein Husebye
(E)
Kohsuke Imai
(K)
Yuval Itan
(Y)
Erich D Jarvis
(ED)
Timokratis Karamitros
(T)
Kai Kisand
(K)
Cheng-Lung Ku
(CL)
Yun Ling
(Y)
Carrie L Lucas
(CL)
László Maródi
(L)
Isabelle Meyts
(I)
Joshua D Milner
(JD)
Kristina Mironska
(K)
Tomohiro Morio
(T)
Lisa F P Ng
(LFP)
Luigi D Notarangelo
(LD)
Cliona O'Farrelly
(C)
Satoshi Okada
(S)
Anna M Planas
(AM)
Lluis Quintana-Murci
(L)
Laurent Renia
(L)
Igor Resnick
(I)
Carlos Rodríguez-Gallego
(C)
Vanessa Sancho-Shimizu
(V)
Anna Sediva
(A)
Mikko R J Seppänen
(MRJ)
Anna Shcherbina
(A)
Ondrej Slaby
(O)
Andrew L Snow
(AL)
Pere Soler-Palacín
(P)
András N Spaan
(AN)
Ivan Tancevski
(I)
Stuart G Tangye
(SG)
Sathishkumar Ramaswamy
(S)
Stuart E Turvey
(SE)
Furkan Uddin
(F)
Mohammed J Uddin
(MJ)
Diederik van de Beek
(D)
Donald C Vinh
(DC)
Mayana Zatz
(M)
Helen C Su
(HC)
Jean-Laurent Casanova
(JL)
Serge Bureau
(S)
Yannick Vacher
(Y)
Anne Gysembergh-Houal
(A)
Lauren Demerville
(L)
Abla Chachoua
(A)
Sebastien Abad
(S)
Radhiya Abassi
(R)
Abdelrafie Abdellaoui
(A)
Abdelkrim Abdelmalek
(A)
Hendy Abdoul
(H)
Helene Abergel
(H)
Fariza Abeud
(F)
Sophie Abgrall
(S)
Noemie Abisror
(N)
Marylise Adechian
(M)
Nordine Aderdour
(N)
Hakeem Farid Admane
(HF)
Frederic Adnet
(F)
Sara Afritt
(S)
Helene Agostini
(H)
Claire Aguilar
(C)
Sophie Agut
(S)
Tommaso Francesco Aiello
(TF)
Marc Ait Kaci
(MA)
Hafid Ait Oufella
(HA)
Gokula Ajeenthiravasan
(G)
Virginie Alauzy
(V)
Fanny Alby-Laurent
(F)
Lucie Allard
(L)
Marie-Alexandra Alyanakian
(MA)
Blanca Amador Borrero
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Lucile Amrouche
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Commentaires et corrections
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