Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

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dc.contributor.authorMatuozzo, Daniela
dc.contributor.authorTalouarn, Estelle
dc.contributor.authorMarchal, Astrid
dc.contributor.authorZhang, Peng
dc.contributor.authorManry, Jeremy
dc.contributor.authorSeeleuthner, Yoann
dc.contributor.authorZhang, Yu
dc.date.accessioned2024-02-23T14:29:08Z
dc.date.available2024-02-23T14:29:08Z
dc.date.issued2023
dc.departmentNEÜen_US
dc.description.abstractBackgroundWe 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 similar to 80% of cases.MethodsWe 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.ResultsNo 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=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare 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.en_US
dc.description.sponsorshipHoward Hughes Medical Institute; Rockefeller University; St. Giles Foundation; National Institutes of Health (NIH) [R01AI088364, R01AI63029]; National Center for Advancing Translational Sciences (NCATS); NIH Clinical and Translational Science Award (CTSA) program [UL1 TR001866]; Emergent Ventures; Mercatus Center at George Mason University; Yale Center for Mendelian Genomics; GSP Coordinating Center - National Human Genome Research Institute (NHGRI) [UM1HG006504, U24HG008956]; Yale High Performance Computing Center [S10OD018521]; Fisher Center for Alzheimer's Research Foundation; JPB Foundation; Meyer Foundation; French National Research Agency (ANR) under the Investments for the Future program [ANR-10-IAHU-01]; Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence [ANR-10-LABX-62-IBEID]; French Foundation for Medical Research (FRM) [EQU201903007798]; ANR GenMISC [ANR-21-COVR-039]; ANR GENVIR [ANR-20-CE93-003]; ANR AABIFNCOV [ANR-20-CO11-0001]; ANR-RHU program COVIF-ERON [ANR-21-RHUS-08]; European Union [824110]; HORIZON-HLTH-2021-DISEASE-04 program [01057100]; Square Foundation; Grandir-Fonds de solidarite pour l'enfance; Fondation du Souffle; SCOR Corporate Foundation for Science; Battersea & Bowery Advisory Group; French Ministry of Higher Education, Research, and Innovation [MESRI-COVID-19]; Institut National de la Sante et de la Recherche Medicale (INSERM); REACTing-INSERM; University of Paris Cite; ORCHESTRA project from the European Union's Horizon 2020 research and innovation program [10101616]; MD-PhD program of the Imagine Institute (Fondation Bettencourt-Schueller); INSERM; REACTing consortium; French Ministry of Health [PHRC 20-0424]; French Ministry of Health; European Commission [RECOVER WP 6]; Fondation AP-HP et Programme Hospitalier de Recherche Clinique [PHRC COVID-19-20-0048]; APHP; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH; Regione Lazio [A0375-2020-36663]; CSL Behring Chair of Primary Immunodeficiencies; KU Leuven C1 Grant [C16/18/007]; VIB GC PID Grant; FWO [G0C8517N, G0B5120N, G0E8420N]; Jeffrey Modell Foundation; European Research Council (ERC) under the European Union [948959]; Swiss National Science Foundation [310030L_197721]; ERN-RITA; Instituto de Salud Carlos III [COV20_01333, COV20_01334, PI20/00876]; Spanish Ministry of Science and Innovation [RTC-2017-6471-1]; European Regional Development Funds, A way of making Europe from the European Union; Cabildo Insular de Tenerife [CGIEU0000219140]; Cabildo Insular de Tenerife (Apuestas cientificas del ITER para colaborar en la lucha contra la COVID-19); Al Jalila Foundation, Dubai, United Arab Emirates [AJF202059]; [ANRS-COV05]; European Research Council (ERC) [948959] Funding Source: European Research Council (ERC); Swiss National Science Foundation (SNF) [310030L_197721] Funding Source: Swiss National Science Foundation (SNF)en_US
dc.description.sponsorshipThe Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI088364 and R01AI63029), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866), a Fast Grant from Emergent Ventures, Mercatus Center at George Mason University, the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956), the Yale High Performance Computing Center (S10OD018521), the Fisher Center for Alzheimer's Research Foundation, the JPB Foundation, the Meyer Foundation, the French National Research Agency (ANR) under the Investments for the Future program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the ANR GenMISC (ANR-21-COVR-039), the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003) ANR AABIFNCOV (ANR-20-CO11-0001) projects, the ANR-RHU program COVIF-ERON (ANR-21-RHUS-08), the European Union's Horizon 2020 research and innovation program under grant agreement No. 824110 (EASI-genomics), the HORIZON-HLTH-2021-DISEASE-04 program under grant agreement 01057100 (UNDINE), the Square Foundation, Grandir-Fonds de solidarite pour l'enfance, Fondation du Souffle, the SCOR Corporate Foundation for Science, the Battersea & Bowery Advisory Group, The French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), Institut National de la Sante et de la Recherche Medicale (INSERM), REACTing-INSERM and the University of Paris Cite. The study was supported by the ORCHESTRA project, which has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 10101616. P Bastard was supported by the MD-PhD program of the Imagine Institute (with the support of the Fondation Bettencourt-Schueller). The French COVID Cohort study group was sponsored by INSERM and supported by the REACTing consortium and by a grant from the French Ministry of Health (Grant PHRC 20-0424). The Cov-Contact Cohort was supported by the REACTing consortium, the French Ministry of Health, and the European Commission (Grant RECOVER WP 6). The COVIDeF study was supported by the French Ministry of Health, Fondation AP-HP et Programme Hospitalier de Recherche Clinique (PHRC COVID-19-20-0048) and was sponsored by APHP. Y.Z., O.M.D., L.D.N., H.C.S. are supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. G.N. and A.N. are supported by Regione Lazio (Research Group Projects 2020) No. A0375-2020-36663, GecoBiomark. I Meyts is a Senior Clinical Investigator at the Research Foundation -Flanders, and is supported by the CSL Behring Chair of Primary Immunodeficiencies, by the KU Leuven C1 Grant C16/18/007, by a VIB GC PID Grant, by the FWO Grants G0C8517N, G0B5120N and G0E8420N and by the Jeffrey Modell Foundation. This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement no. 948959). This work is supported by the Swiss National Science Foundation (grant #310030L_197721 to JF). This work is supported by ERN-RITA.; The Canarian Sequencing Hub is funded by Instituto de Salud Carlos III (COV20_01333, and COV20_01334, and PI20/00876) and Spanish Ministry of Science and Innovation (RTC-2017-6471-1; AEI/FEDER, UE), co-financed by the European Regional Development Funds, A way of making Europe from the European Union, and Cabildo Insular de Tenerife (CGIEU0000219140 and Apuestas cientificas del ITER para colaborar en la lucha contra la COVID-19). This work was funded, at least in part, by grant AJF202059 from Al Jalila Foundation, Dubai, United Arab Emirates. Sample processing at IrsiCaixa was possible thanks to the crowdfunding initiative YoMeCorono. We thank I Erkizia, E Grau, M Massanella, and J Guitart from the IrsiCaixa and Hospital Germans Trias i Pujol (Badalona, Spain) for sample collection, handling and processing.en_US
dc.identifier.doi10.1186/s13073-023-01173-8
dc.identifier.issn1756-994X
dc.identifier.issue1en_US
dc.identifier.pmid37020259en_US
dc.identifier.scopus2-s2.0-85160044322en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.1186/s13073-023-01173-8
dc.identifier.urihttps://hdl.handle.net/20.500.12452/14552
dc.identifier.volume15en_US
dc.identifier.wosWOS:001022167700001en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherBmcen_US
dc.relation.ispartofGenome Medicineen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectRare Variantsen_US
dc.subjectCovid-19en_US
dc.subjectImmunityen_US
dc.subjectType I Interferonen_US
dc.titleRare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19en_US
dc.typeArticleen_US

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