Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19
Abstract 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 d...
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-04-01
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| Series: | Genome Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13073-023-01173-8 |
| _version_ | 1827388276231634944 |
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| author | Daniela Matuozzo Estelle Talouarn Astrid Marchal Peng Zhang Jeremy Manry Yoann Seeleuthner Yu Zhang Alexandre Bolze Matthieu Chaldebas Baptiste Milisavljevic Adrian Gervais Paul Bastard Takaki Asano Lucy Bizien Federica Barzaghi Hassan Abolhassani Ahmad Abou Tayoun Alessandro Aiuti Ilad Alavi Darazam Luis M. Allende Rebeca Alonso-Arias Andrés Augusto Arias Gokhan Aytekin Peter Bergman Simone Bondesan Yenan T. Bryceson Ingrid G. Bustos Oscar Cabrera-Marante Sheila Carcel Paola Carrera Giorgio Casari Khalil Chaïbi Roger Colobran Antonio Condino-Neto Laura E. Covill Ottavia M. Delmonte Loubna El Zein Carlos Flores Peter K. Gregersen Marta Gut Filomeen Haerynck Rabih Halwani Selda Hancerli Lennart Hammarström Nevin Hatipoğlu Adem Karbuz Sevgi Keles Christèle Kyheng Rafael Leon-Lopez Jose Luis Franco Davood Mansouri Javier Martinez-Picado Ozge Metin Akcan Isabelle Migeotte Pierre-Emmanuel Morange Guillaume Morelle Andrea Martin-Nalda Giuseppe Novelli Antonio Novelli Tayfun Ozcelik Figen Palabiyik Qiang Pan-Hammarström Rebeca Pérez de Diego Laura Planas-Serra Daniel E. Pleguezuelo Carolina Prando Aurora Pujol Luis Felipe Reyes Jacques G. Rivière Carlos Rodriguez-Gallego Julian Rojas Patrizia Rovere-Querini Agatha Schlüter Mohammad Shahrooei Ali Sobh Pere Soler-Palacin Yacine Tandjaoui-Lambiotte Imran Tipu Cristina Tresoldi Jesus Troya Diederik van de Beek Mayana Zatz Pawel Zawadzki Saleh Zaid Al-Muhsen Mohammed Faraj Alosaimi Fahad M. Alsohime Hagit Baris-Feldman Manish J. Butte Stefan N. Constantinescu Megan A. Cooper Clifton L. Dalgard Jacques Fellay James R. Heath Yu-Lung Lau Richard P. Lifton Tom Maniatis Trine H. Mogensen Horst von Bernuth Alban Lermine Michel Vidaud Anne Boland Jean-François Deleuze Robert Nussbaum Amanda Kahn-Kirby France Mentre Sarah Tubiana Guy Gorochov Florence Tubach Pierre Hausfater COVID Human Genetic Effort COVIDeF Study Group French COVID Cohort Study Group CoV-Contact Cohort COVID-STORM Clinicians COVID Clinicians Orchestra Working Group Amsterdam UMC Covid-19 Biobank NIAID-USUHS COVID Study Group Isabelle Meyts Shen-Ying Zhang Anne Puel Luigi D. Notarangelo Stephanie Boisson-Dupuis Helen C. Su Bertrand Boisson Emmanuelle Jouanguy Jean-Laurent Casanova Qian Zhang Laurent Abel Aurélie Cobat |
| author_facet | Daniela Matuozzo Estelle Talouarn Astrid Marchal Peng Zhang Jeremy Manry Yoann Seeleuthner Yu Zhang Alexandre Bolze Matthieu Chaldebas Baptiste Milisavljevic Adrian Gervais Paul Bastard Takaki Asano Lucy Bizien Federica Barzaghi Hassan Abolhassani Ahmad Abou Tayoun Alessandro Aiuti Ilad Alavi Darazam Luis M. Allende Rebeca Alonso-Arias Andrés Augusto Arias Gokhan Aytekin Peter Bergman Simone Bondesan Yenan T. Bryceson Ingrid G. Bustos Oscar Cabrera-Marante Sheila Carcel Paola Carrera Giorgio Casari Khalil Chaïbi Roger Colobran Antonio Condino-Neto Laura E. Covill Ottavia M. Delmonte Loubna El Zein Carlos Flores Peter K. Gregersen Marta Gut Filomeen Haerynck Rabih Halwani Selda Hancerli Lennart Hammarström Nevin Hatipoğlu Adem Karbuz Sevgi Keles Christèle Kyheng Rafael Leon-Lopez Jose Luis Franco Davood Mansouri Javier Martinez-Picado Ozge Metin Akcan Isabelle Migeotte Pierre-Emmanuel Morange Guillaume Morelle Andrea Martin-Nalda Giuseppe Novelli Antonio Novelli Tayfun Ozcelik Figen Palabiyik Qiang Pan-Hammarström Rebeca Pérez de Diego Laura Planas-Serra Daniel E. Pleguezuelo Carolina Prando Aurora Pujol Luis Felipe Reyes Jacques G. Rivière Carlos Rodriguez-Gallego Julian Rojas Patrizia Rovere-Querini Agatha Schlüter Mohammad Shahrooei Ali Sobh Pere Soler-Palacin Yacine Tandjaoui-Lambiotte Imran Tipu Cristina Tresoldi Jesus Troya Diederik van de Beek Mayana Zatz Pawel Zawadzki Saleh Zaid Al-Muhsen Mohammed Faraj Alosaimi Fahad M. Alsohime Hagit Baris-Feldman Manish J. Butte Stefan N. Constantinescu Megan A. Cooper Clifton L. Dalgard Jacques Fellay James R. Heath Yu-Lung Lau Richard P. Lifton Tom Maniatis Trine H. Mogensen Horst von Bernuth Alban Lermine Michel Vidaud Anne Boland Jean-François Deleuze Robert Nussbaum Amanda Kahn-Kirby France Mentre Sarah Tubiana Guy Gorochov Florence Tubach Pierre Hausfater COVID Human Genetic Effort COVIDeF Study Group French COVID Cohort Study Group CoV-Contact Cohort COVID-STORM Clinicians COVID Clinicians Orchestra Working Group Amsterdam UMC Covid-19 Biobank NIAID-USUHS COVID Study Group Isabelle Meyts Shen-Ying Zhang Anne Puel Luigi D. Notarangelo Stephanie Boisson-Dupuis Helen C. Su Bertrand Boisson Emmanuelle Jouanguy Jean-Laurent Casanova Qian Zhang Laurent Abel Aurélie Cobat |
| author_sort | Daniela Matuozzo |
| collection | DOAJ |
| description | Abstract 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 × 10−4) 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 = 2.1 × 10−4). 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 = 3.4 × 10−3), 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 = 7.7 × 10−8). 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 = 1.68 × 10−5). 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. |
| first_indexed | 2024-03-08T16:15:22Z |
| format | Article |
| id | doaj.art-86e4db2aa39842caa8f2f5c9e6d95290 |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-03-08T16:15:22Z |
| publishDate | 2023-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-86e4db2aa39842caa8f2f5c9e6d952902024-01-07T12:37:52ZengBMCGenome Medicine1756-994X2023-04-0115112510.1186/s13073-023-01173-8Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19Daniela Matuozzo0Estelle Talouarn1Astrid Marchal2Peng Zhang3Jeremy Manry4Yoann Seeleuthner5Yu Zhang6Alexandre Bolze7Matthieu Chaldebas8Baptiste Milisavljevic9Adrian Gervais10Paul Bastard11Takaki Asano12Lucy Bizien13Federica Barzaghi14Hassan Abolhassani15Ahmad Abou Tayoun16Alessandro Aiuti17Ilad Alavi Darazam18Luis M. Allende19Rebeca Alonso-Arias20Andrés Augusto Arias21Gokhan Aytekin22Peter Bergman23Simone Bondesan24Yenan T. Bryceson25Ingrid G. Bustos26Oscar Cabrera-Marante27Sheila Carcel28Paola Carrera29Giorgio Casari30Khalil Chaïbi31Roger Colobran32Antonio Condino-Neto33Laura E. Covill34Ottavia M. Delmonte35Loubna El Zein36Carlos Flores37Peter K. Gregersen38Marta Gut39Filomeen Haerynck40Rabih Halwani41Selda Hancerli42Lennart Hammarström43Nevin Hatipoğlu44Adem Karbuz45Sevgi Keles46Christèle Kyheng47Rafael Leon-Lopez48Jose Luis Franco49Davood Mansouri50Javier Martinez-Picado51Ozge Metin Akcan52Isabelle Migeotte53Pierre-Emmanuel Morange54Guillaume Morelle55Andrea Martin-Nalda56Giuseppe Novelli57Antonio Novelli58Tayfun Ozcelik59Figen Palabiyik60Qiang Pan-Hammarström61Rebeca Pérez de Diego62Laura Planas-Serra63Daniel E. Pleguezuelo64Carolina Prando65Aurora Pujol66Luis Felipe Reyes67Jacques G. Rivière68Carlos Rodriguez-Gallego69Julian Rojas70Patrizia Rovere-Querini71Agatha Schlüter72Mohammad Shahrooei73Ali Sobh74Pere Soler-Palacin75Yacine Tandjaoui-Lambiotte76Imran Tipu77Cristina Tresoldi78Jesus Troya79Diederik van de Beek80Mayana Zatz81Pawel Zawadzki82Saleh Zaid Al-Muhsen83Mohammed Faraj Alosaimi84Fahad M. Alsohime85Hagit Baris-Feldman86Manish J. Butte87Stefan N. Constantinescu88Megan A. Cooper89Clifton L. Dalgard90Jacques Fellay91James R. Heath92Yu-Lung Lau93Richard P. Lifton94Tom Maniatis95Trine H. Mogensen96Horst von Bernuth97Alban Lermine98Michel Vidaud99Anne Boland100Jean-François Deleuze101Robert Nussbaum102Amanda Kahn-Kirby103France Mentre104Sarah Tubiana105Guy Gorochov106Florence Tubach107Pierre Hausfater108COVID Human Genetic EffortCOVIDeF Study GroupFrench COVID Cohort Study GroupCoV-Contact CohortCOVID-STORM CliniciansCOVID CliniciansOrchestra Working GroupAmsterdam UMC Covid-19 BiobankNIAID-USUHS COVID Study GroupIsabelle Meyts109Shen-Ying Zhang110Anne Puel111Luigi D. Notarangelo112Stephanie Boisson-Dupuis113Helen C. Su114Bertrand Boisson115Emmanuelle Jouanguy116Jean-Laurent Casanova117Qian Zhang118Laurent Abel119Aurélie Cobat120Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller UniversityLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAIDHelixSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller UniversitySt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller UniversityLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller UniversityLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163Department of Paediatric Immunohematology, IRCCS San Raffaele Scientific InstituteDepartment of Biosciences and Nutrition, Karolinska InstituteGenomics Center of Excellence, Al Jalila Children’s Specialty HospitalSan Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCSS San Raffaele Scientific InstituteInfectious Diseases and Tropical Medicine Research Center, Shahid Beheshti University of Medical SciencesImmunology Department, University Hospital 12 de Octubre, Research Institute imas12 and Complutense UniversityImmunology Department, Hospital Universitario Central de Asturias; Health Research Institute of Principality of AsturiasSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller UniversityDeparment of Internal Medicine, Division of Allergy and Immunology, Konya City HospitalDepartment of Infectious Diseases, The Immunodeficiency Unit, Karolinska University HospitalClinical Genomics, IRCSS San Raffaele Scientific InstituteDepartment of Medicine, Centre for Hematology and Regenerative Medicine, Karolinska InstituteUniversidad de La SabanaInstitute of Biomedical Research of IdiPAZ, University Hospital “La Paz”Unidad de Gestión Clínica de Cuidados Intensivos, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Universidad de Córdoba (UCO)Clinical Genomics, IRCSS San Raffaele Scientific InstituteDivision of Genetics and Cell Biology, Genome-Phenome Relationship, San Raffaele HospitalIntensive Care Unit Department, Avicenne Hospital, Assistance Publique-Hôpitaux de ParisJeffrey Modell Diagnostic and Research Center for Primary ImmunodeficienciesDepartment of Immunology, Institute of Biomedical Sciences, University of São PauloDepartment of Medicine, Centre for Hematology and Regenerative Medicine, Karolinska InstituteLaboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAIDBiology Department, Lebanese UniversityGenomics Division, Institute of Technology and Renewable Energies (ITER)Feinstein Institute for Medical Research, Northwell Health USACNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST)Department of Internal Diseases and Pediatrics, Primary Immune Deficiency Research Laboratory, Centre for Primary Immunodeficiency Ghent, Jeffrey Modell Diagnosis and Research Centre Research Institute for Medical and Health Sciences, University of SharjahDepartment of Pediatrics (Infectious Diseases), Istanbul Faculty of Medicine, Istanbul UniversityDepartment of Biosciences and Nutrition, Karolinska InstitutePediatric Infectious Diseases Unit, Bakirkoy Dr Sadi Konuk Training and Research Hospital, University of Health SciencesDepartment of Pediatric Infectious Disease, Dr. Cemil Tascioglu City HospitalMeram Medical Faculty, Pediatric Infectious Diseases Department, Necmettin Erbakan UniversityDepartment of General Paediatrics, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, University of Paris SaclayUnidad de Gestión Clínica de Cuidados Intensivos, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Universidad de Córdoba (UCO)Primary Immunodeficiencies Group, Department of Microbiology and Parasitology, School of Medicine, University of Antioquia UDEAThe Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical SciencesIrsiCaixa AIDS Research Institute and Institute for Health Science Research Germans Trias I Pujol (IGTP)Meram Medical Faculty, Pediatric Infectious Diseases Department, Necmettin Erbakan UniversityCentre de Génétique Humaine de L’Université Libre de Bruxelles, Hôpital ErasmeLaboratory of Haematology, La Timone HospitalDepartment of General Paediatrics, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, University of Paris SaclayJeffrey Modell Diagnostic and Research Center for Primary ImmunodeficienciesDepartment of Biomedicine and Prevention, Tor Vergata University of RomeLaboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital, IRCCSDepartment of Molecular Biology and Genetics, Bilkent UniversityPediatric Infectious Diseases Unit, Bakirkoy Dr Sadi Konuk Training and Research Hospital, University of Health SciencesDepartment of Biosciences and Nutrition, Karolinska InstituteLaboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, University Hospital “La Paz”Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)Immunology Department, University Hospital 12 de Octubre, Research Institute imas12 and Complutense UniversityFaculdades Pequeno Príncipe, Instituto de Pesquisa Pelé Pequeno PríncipeCatalan Institution of Research and Advanced Studies (ICREA)Universidad de La SabanaJeffrey Modell Diagnostic and Research Center for Primary ImmunodeficienciesDepartment of Immunology, University Hospital of Gran Canaria Dr. Negrin, Canarian Health SystemPrimary Immunodeficiencies Group, Department of Microbiology and Parasitology, School of Medicine, University of Antioquia UDEAVita-Salute San Raffaele UniversityNeurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)Specialized Immunology Laboratory of Dr Shahrooei, Sina Medical ComplexDepartment of Pediatrics, Mansoura University Children’s Hospital, Mansoura University Faculty of MedicineJeffrey Modell Diagnostic and Research Center for Primary ImmunodeficienciesHypoxia and Lung, INSERM U1272, Avicenne Hospital, Assistance Publique-Hôpitaux de ParisDepartment of Life Sciences, School of Science, University of Management and TechnologyDivision of Immunology, Transplantation and Infectious Diseases, IRCCS Ospedale San RaffaeleDepartment of Internal Medicine, Infanta Leonor University HospitalDepartment of Neurology, Amsterdam UMC, Amsterdam NeuroscienceBiosciences Institute, University of São PauloGordion Bioscience IncDepartment of Pediatrics, Immunology Research Laboratory, College of Medicine and King Saud University Medical City, King Saud UniversityDepartment of Pediatrics, Immunology Research Laboratory, College of Medicine and King Saud University Medical City, King Saud UniversityDepartment of Pediatrics, Immunology Research Laboratory, College of Medicine and King Saud University Medical City, King Saud UniversityThe Genetics Institute, Tel Aviv Sourasky Medical CenterDepartments of Pediatrics and Microbiology, Immunology, and Molecular Genetics, Division of Immunology, Allergy, and Rheumatology, University of California Los AngelesLudwig Institute for Cancer ResearchDepartment of Pediatrics, Division of Rheumatology/Immunology, Washington University in St. LouisThe American Genome Center, Uniformed Services University of the Health SciencesSchool of Life Sciences, École Polytechnique Fédérale de LausanneInstitute for Systems BiologyDepartment of Paediatrics and Adolescent Medicine, Queen Mary Hospital, Li Ka Shing Faculty of Medicine, University of Hong KongLaboratory of Genetics and Genomics, The Rockefeller UniversityZukerman Mind Brain Behavior Institute, Columbia UniversityDepartment of Biomedicine, Aarhus UniversityDepartment of Paediatric Respiratory Medicine, Immunology, and Critical Care Medicine, Charité Universitätsmedizin BerlinLaboratoire de Biologie Médicale Multisites SeqoiaLaboratoire de Biologie Médicale Multisites SeqoiaUniversité Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH)Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH)InvitaeInvitaeUnité de Recherche Clinique, Hôpital Bichat, Assistance Publique-Hôpitaux de ParisCentre d’Investigation Clinique, Hôpital Bichat, Assistance Publique-Hôpitaux de ParisSorbonne Université, INSERM Centre d’Immunologie et des Maladies Infectieuses, CIMI-Paris, Département d’immunologie Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de ParisSorbonne Université, INSERM, Institut Pierre Louis d’Epidémiologie et de Santé Publique, AP-HP, Hôpital Pitié Salpêtrière, Département de Santé Publique, Unité de Recherche Clinique PSL-CFX , CIC-1901Emergency Department, Hôpital Pitié-Salpêtrière, APHP-Sorbonne UniversitéDepartment of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, KU LeuvenLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163Laboratory of Host Defenses, NIAID, National Institutes of HealthLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAIDLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163Abstract 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 × 10−4) 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 = 2.1 × 10−4). 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 = 3.4 × 10−3), 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 = 7.7 × 10−8). 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 = 1.68 × 10−5). 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.https://doi.org/10.1186/s13073-023-01173-8Rare variantsCOVID-19ImmunityType I interferon |
| spellingShingle | Daniela Matuozzo Estelle Talouarn Astrid Marchal Peng Zhang Jeremy Manry Yoann Seeleuthner Yu Zhang Alexandre Bolze Matthieu Chaldebas Baptiste Milisavljevic Adrian Gervais Paul Bastard Takaki Asano Lucy Bizien Federica Barzaghi Hassan Abolhassani Ahmad Abou Tayoun Alessandro Aiuti Ilad Alavi Darazam Luis M. Allende Rebeca Alonso-Arias Andrés Augusto Arias Gokhan Aytekin Peter Bergman Simone Bondesan Yenan T. Bryceson Ingrid G. Bustos Oscar Cabrera-Marante Sheila Carcel Paola Carrera Giorgio Casari Khalil Chaïbi Roger Colobran Antonio Condino-Neto Laura E. Covill Ottavia M. Delmonte Loubna El Zein Carlos Flores Peter K. Gregersen Marta Gut Filomeen Haerynck Rabih Halwani Selda Hancerli Lennart Hammarström Nevin Hatipoğlu Adem Karbuz Sevgi Keles Christèle Kyheng Rafael Leon-Lopez Jose Luis Franco Davood Mansouri Javier Martinez-Picado Ozge Metin Akcan Isabelle Migeotte Pierre-Emmanuel Morange Guillaume Morelle Andrea Martin-Nalda Giuseppe Novelli Antonio Novelli Tayfun Ozcelik Figen Palabiyik Qiang Pan-Hammarström Rebeca Pérez de Diego Laura Planas-Serra Daniel E. Pleguezuelo Carolina Prando Aurora Pujol Luis Felipe Reyes Jacques G. Rivière Carlos Rodriguez-Gallego Julian Rojas Patrizia Rovere-Querini Agatha Schlüter Mohammad Shahrooei Ali Sobh Pere Soler-Palacin Yacine Tandjaoui-Lambiotte Imran Tipu Cristina Tresoldi Jesus Troya Diederik van de Beek Mayana Zatz Pawel Zawadzki Saleh Zaid Al-Muhsen Mohammed Faraj Alosaimi Fahad M. Alsohime Hagit Baris-Feldman Manish J. Butte Stefan N. Constantinescu Megan A. Cooper Clifton L. Dalgard Jacques Fellay James R. Heath Yu-Lung Lau Richard P. Lifton Tom Maniatis Trine H. Mogensen Horst von Bernuth Alban Lermine Michel Vidaud Anne Boland Jean-François Deleuze Robert Nussbaum Amanda Kahn-Kirby France Mentre Sarah Tubiana Guy Gorochov Florence Tubach Pierre Hausfater COVID Human Genetic Effort COVIDeF Study Group French COVID Cohort Study Group CoV-Contact Cohort COVID-STORM Clinicians COVID Clinicians Orchestra Working Group Amsterdam UMC Covid-19 Biobank NIAID-USUHS COVID Study Group Isabelle Meyts Shen-Ying Zhang Anne Puel Luigi D. Notarangelo Stephanie Boisson-Dupuis Helen C. Su Bertrand Boisson Emmanuelle Jouanguy Jean-Laurent Casanova Qian Zhang Laurent Abel Aurélie Cobat Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19 Genome Medicine Rare variants COVID-19 Immunity Type I interferon |
| title | Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19 |
| title_full | Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19 |
| title_fullStr | Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19 |
| title_full_unstemmed | Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19 |
| title_short | Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19 |
| title_sort | rare predicted loss of function variants of type i ifn immunity genes are associated with life threatening covid 19 |
| topic | Rare variants COVID-19 Immunity Type I interferon |
| url | https://doi.org/10.1186/s13073-023-01173-8 |
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