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Rare Predicted Loss-Of-Function Variants of Type I Ifn Immunity Genes Are Associated With Life-Threatening Covid-19 Publisher



Matuozzo D1, 2 ; Talouarn E1, 2 ; Marchal A1, 2 ; Zhang P3 ; Manry J1, 2 ; Seeleuthner Y1, 2 ; Zhang Y4 ; Bolze A5 ; Chaldebas M3 ; Milisavljevic B3 ; Gervais A1, 2 ; Bastard P1, 2, 3, 6 ; Asano T3 ; Bizien L1, 2 Show All Authors
Authors
  1. Matuozzo D1, 2
  2. Talouarn E1, 2
  3. Marchal A1, 2
  4. Zhang P3
  5. Manry J1, 2
  6. Seeleuthner Y1, 2
  7. Zhang Y4
  8. Bolze A5
  9. Chaldebas M3
  10. Milisavljevic B3
  11. Gervais A1, 2
  12. Bastard P1, 2, 3, 6
  13. Asano T3
  14. Bizien L1, 2
  15. Barzaghi F7
  16. Abolhassani H8, 9
  17. Abou Tayoun A10, 11
  18. Aiuti A12, 13
  19. Alavi Darazam I14, 15
  20. Allende LM16
  21. Alonsoarias R17
  22. Arias AA3, 19, 20
  23. Aytekin G21
  24. Bergman P22, 23
  25. Bondesan S24
  26. Bryceson YT25
  27. Bustos IG26
  28. Cabreramarante O27
  29. Carcel S28
  30. Carrera P24
  31. Casari G29, 30
  32. Chaibi K31, 32
  33. Colobran R33, 34, 35
  34. Condinoneto A36
  35. Covill LE25
  36. Delmonte OM4
  37. El Zein L37
  38. Flores C38, 39, 40, 41
  39. Gregersen PK42
  40. Gut M43
  41. Haerynck F44
  42. Halwani R45
  43. Hancerli S46
  44. Hammarstrom L8
  45. Hatipoglu N47
  46. Karbuz A48
  47. Keles S49
  48. Kyheng C50
  49. Leonlopez R28
  50. Franco JL51
  51. Mansouri D52, 53, 54
  52. Martinezpicado J55, 57, 58, 59
  53. Metin Akcan O49
  54. Migeotte I60
  55. Morange PE61, 62
  56. Morelle G50
  57. Martinnalda A33, 63, 64
  58. Novelli G65, 66
  59. Novelli A67
  60. Palabiyik F47
  61. Panhammarstrom Q8
  62. De Diego RP69
  63. Planasserra L70, 71
  64. Pleguezuelo DE16
  65. Prando C72
  66. Pujol A58, 70, 71
  67. Reyes LF26
  68. Riviere JG33, 63, 64
  69. Rodriguezgallego C73, 74
  70. Rojas J51
  71. Roverequerini P13, 75
  72. Schluter A70, 71
  73. Shahrooei M76, 77
  74. Sobh A78
  75. Solerpalacin P33, 63, 64
  76. Tandjaouilambiotte Y79
  77. Tipu I80
  78. Tresoldi C81
  79. Troya J82
  80. Van De Beek D83
  81. Zatz M84
  82. Zawadzki P85, 86
  83. Almuhsen SZ87
  84. Alosaimi MF87
  85. Alsohime FM87
  86. Barisfeldman H88, 89
  87. Butte MJ90
  88. Constantinescu SN91, 92, 93, 94
  89. Cooper MA95
  90. Dalgard CL96, 97
  91. Fellay J98, 99, 100
  92. Heath JR101
  93. Lau YL102
  94. Lifton RP103, 104, 105
  95. Maniatis T106, 107
  96. Mogensen TH108, 109
  97. Von Bernuth H110
  98. Lermine A111
  99. Vidaud M111
  100. Boland A112
  101. Deleuze JF112
  102. Nussbaum R113
  103. Kahnkirby A113
  104. Mentre F114
  105. Tubiana S115
  106. Gorochov G116
  107. Tubach F117
  108. Hausfater P118, 119
  109. Casanova JL1, 2, 3, 122
  110. Ozcelik T68
  111. Meyts I120
  112. Zhang SY1, 2, 3
  113. Puel A1, 2, 3
  114. Notarangelo LD121
  115. Boissondupuis S1, 2, 3
  116. Su HC4
  117. Boisson B1, 2, 3
  118. Jouanguy E1, 2, 3
  119. Zhang Q1, 2, 3
  120. Abel L1, 2, 3
  121. Cobat A1, 2, 3
Show Affiliations
Authors Affiliations
  1. 1. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
  2. 2. University Paris Cite, Imagine Institute, Paris, France
  3. 3. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, United States
  4. 4. Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, Bethesda, MD, United States
  5. 5. Helix, San Mateo, CA, United States
  6. 6. Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, Assistance Publique-Hopitaux de Paris (AP-HP), Paris, France
  7. 7. Department of Paediatric Immunohematology, IRCCS San Raffaele Scientific Institute, Milan, Italy
  8. 8. Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden
  9. 9. Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran, Iran
  10. 10. Genomics Center of Excellence, Al Jalila Children’s Specialty Hospital, Dubai, United Arab Emirates
  11. 11. Center for Genomic Discovery, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
  12. 12. San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCSS San Raffaele Scientific Institute, Milan, Italy
  13. 13. Vita-Salute San Raffaele University, Milan, Italy
  14. 14. Infectious Diseases and Tropical Medicine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  15. 15. Department of Infectious Diseases and Tropical Medicine, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  16. 16. Immunology Department, University Hospital 12 de Octubre, Research Institute imas12 and Complutense University, Madrid, Spain
  17. 17. Immunology Department, Hospital Universitario Central de Asturias
  18. 18. Health Research Institute of Principality of Asturias, Oviedo, Spain
  19. 19. Department of Microbiology and Parasitology, Primary Immunodeficiencies Group, School of Medicine, University of Antioquia UdeA, Medellin, 050010, Colombia
  20. 20. School of Microbiology, University of Antioquia UdeA, Medellin, 050010, Colombia
  21. 21. Deparment of Internal Medicine, Division of Allergy and Immunology, Konya City Hospital, Konya, Turkey
  22. 22. Department of Infectious Diseases, The Immunodeficiency Unit, Karolinska University Hospital, Stockholm, Sweden
  23. 23. Department of Laboratory Medicine, Division of Clinical Immunology, Stockholm, Sweden
  24. 24. Clinical Genomics, IRCSS San Raffaele Scientific Institute, Milan, Italy
  25. 25. Department of Medicine, Centre for Hematology and Regenerative Medicine, Karolinska Institute, Stockholm, Sweden
  26. 26. Universidad de La Sabana, Chia, Colombia
  27. 27. Institute of Biomedical Research of IdiPAZ, University Hospital “La Paz�, Madrid, Spain
  28. 28. Unidad de Gestion Clinica de Cuidados Intensivos, Instituto Maimonides de Investigacion Biomedica de Cordoba (IMIBIC), Hospital Universitario Reina Sofia, Universidad de Cordoba (UCO), Cordoba, Spain
  29. 29. Division of Genetics and Cell Biology, Genome-Phenome Relationship, San Raffaele Hospital, Milan, Italy
  30. 30. School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
  31. 31. Intensive Care Unit Department, Avicenne Hospital, Assistance Publique-Hopitaux de Paris, Bobigny, France
  32. 32. Common and Rare Kidney Diseases, Sorbonne University, INSERM UMR-S 1155, Paris, France
  33. 33. Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Catalonia, Barcelona, Spain
  34. 34. Translational Immunology Research Group, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron University Hospital (HUVH), Vall d’Hebron Barcelona Hospital Campus, Catalonia, Barcelona, Spain
  35. 35. Genetics Department, Immunology Division, Vall d’Hebron University Hospital (HUVH), Vall d’Hebron Barcelona Hospital Campus, Autonomous University of Barcelona (UAB), Catalonia, Barcelona, Spain
  36. 36. Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
  37. 37. Biology Department, Lebanese University, Beirut, Lebanon
  38. 38. Genomics Division, Institute of Technology and Renewable Energies (ITER), Santa Cruz de Tenerife, Spain
  39. 39. CIBER de Enfermedades Respiratorias, Carlos III Health Institute, Madrid, Spain
  40. 40. Research Unit, University Hospital of Ntra. Sra. de Candelaria, Santa Cruz de Tenerife, Spain
  41. 41. Faculty of Health Sciences, University of Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain
  42. 42. Feinstein Institute for Medical Research, Northwell Health USA, Manhasset, NY, United States
  43. 43. CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
  44. 44. Department of Internal Diseases and Pediatrics, Primary Immune Deficiency Research Laboratory, Centre for Primary Immunodeficiency Ghent, Jeffrey Modell Diagnosis and Research Centre, Ghent, Belgium
  45. 45. Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
  46. 46. Department of Pediatrics (Infectious Diseases), Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
  47. 47. Pediatric Infectious Diseases Unit, Bakirkoy Dr Sadi Konuk Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
  48. 48. Department of Pediatric Infectious Disease, Dr. Cemil Tascioglu City Hospital, Istanbul, Turkey
  49. 49. Meram Medical Faculty, Pediatric Infectious Diseases Department, Necmettin Erbakan University, Konya, Turkey
  50. 50. Department of General Paediatrics, Hopital Bicetre, Assistance Publique-Hopitaux de Paris, University of Paris Saclay, Le Kremlin-Bicetre, France
  51. 51. Primary Immunodeficiencies Group, Department of Microbiology and Parasitology, School of Medicine, University of Antioquia UDEA, Medellin, 050010, Colombia
  52. 52. The Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  53. 53. Department of Clinical Immunology and Infectious Diseases, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  54. 54. Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  55. 55. IrsiCaixa AIDS Research Institute and Institute for Health Science Research Germans Trias I Pujol (IGTP), Badalona, Spain
  56. 56. Institute for Health Science Research Germans Trias I Pujol (IGTP), Badalona, Spain
  57. 57. Department of Infectious Diseases and Immunity, University of Vic-Central University of Catalonia, Vic, Spain
  58. 58. Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain
  59. 59. Consorcio Centro de Investigacion Biomedica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
  60. 60. Centre de Genetique Humaine de L’Universite Libre de Bruxelles, Hopital Erasme, Brussels, Belgium
  61. 61. Laboratory of Haematology, La Timone Hospital, Marseille, France
  62. 62. C2VN, INSERM, INRAE, Aix-Marseille University, Marseille, France
  63. 63. Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron University Hospital (HUVH), Vall d’Hebron Barcelona Hospital Campus, Autonomous University of Barcelona (UAB), Catalonia, Barcelona, Spain
  64. 64. Infection and Immunity in Pediatric Patients Research Group, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron University Hospital (HUVH), Vall d’Hebron Barcelona Hospital Campus, Catalonia, Barcelona, Spain
  65. 65. Department of Biomedicine and Prevention, Tor Vergata University of Rome, Rome, Italy
  66. 66. IRCCS Neuromed, Pozzilli, Italy
  67. 67. Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesu Children Hospital, IRCCS, Rome, Italy
  68. 68. Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey
  69. 69. Laboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, University Hospital “La Paz�, Madrid, Spain
  70. 70. Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Catalonia, Barcelona, Spain
  71. 71. Center for Biomedical Research On Rare Diseases (CIBERER), ISCIII, Madrid, Spain
  72. 72. Faculdades Pequeno Principe, Instituto de Pesquisa Pele Pequeno Principe, Curitiba, Brazil
  73. 73. Department of Immunology, University Hospital of Gran Canaria Dr. Negrin, Canarian Health System, Las Palmas de Gran Canaria, Spain
  74. 74. Department of Clinical Sciences, University of Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain
  75. 75. Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
  76. 76. Specialized Immunology Laboratory of Dr Shahrooei, Sina Medical Complex, Ahvaz, Iran
  77. 77. Department of Microbiology and Immunology, Clinical and Diagnostic Immunology, KU Leuven, Leuven, Belgium
  78. 78. Department of Pediatrics, Mansoura University Children’s Hospital, Mansoura University Faculty of Medicine, Mansoura, Egypt
  79. 79. Hypoxia and Lung, INSERM U1272, Avicenne Hospital, Assistance Publique-Hopitaux de Paris, Bobigny, France
  80. 80. Department of Life Sciences, School of Science, University of Management and Technology, Lahore, Pakistan
  81. 81. Division of Immunology, Transplantation and Infectious Diseases, IRCCS Ospedale San Raffaele, Milan, Italy
  82. 82. Department of Internal Medicine, Infanta Leonor University Hospital, Madrid, Spain
  83. 83. Department of Neurology, Amsterdam UMC, Amsterdam Neuroscience, Amsterdam, Netherlands
  84. 84. Biosciences Institute, University of Sao Paulo, Sao Paulo, Brazil
  85. 85. Gordion Bioscience Inc, Cambridge, MA, United States
  86. 86. Faculty of Physics, Adam Mickiewicz University, Poznan, Poland
  87. 87. Department of Pediatrics, Immunology Research Laboratory, College of Medicine and King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia
  88. 88. The Genetics Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
  89. 89. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
  90. 90. Departments of Pediatrics and Microbiology, Immunology, and Molecular Genetics, Division of Immunology, Allergy, and Rheumatology, University of California Los Angeles, Los Angeles, CA, United States
  91. 91. Ludwig Institute for Cancer Research, Brussels, Belgium
  92. 92. SIGN Unit, de Duve Institute, Universite Catholique de Louvain, Brussels, Belgium
  93. 93. WELBIO (Walloon Excellence in Life Sciences and Biotechnology), Brussels, Belgium
  94. 94. Nuffield Department of Medicine, Ludwig Institute for Cancer Research, Oxford University, Oxford, United Kingdom
  95. 95. Department of Pediatrics, Division of Rheumatology/Immunology, Washington University in St. Louis, St. Louis, MO, United States
  96. 96. The American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, United States
  97. 97. Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
  98. 98. School of Life Sciences, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland
  99. 99. Swiss Institute of Bioinformatics, Lausanne, Switzerland
  100. 100. Precision Medicine Unit, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
  101. 101. Institute for Systems Biology, Seattle, WA, United States
  102. 102. Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
  103. 103. Laboratory of Genetics and Genomics, The Rockefeller University, New York, NY, United States
  104. 104. Department of Genetics, Yale University School of Medicine, New Haven, CT, United States
  105. 105. Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT, United States
  106. 106. Zukerman Mind Brain Behavior Institute, Columbia University, New York, NY, United States
  107. 107. New York Genome Center, New York, NY, United States
  108. 108. Department of Biomedicine, Aarhus University, Aarhus, Denmark
  109. 109. Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
  110. 110. Department of Paediatric Respiratory Medicine, Immunology, and Critical Care Medicine, Charite Universitatsmedizin Berlin, Berlin, Germany
  111. 111. Laboratoire de Biologie Medicale Multisites Seqoia, Paris, MG2025, MG2025, France
  112. 112. Universite Paris-Saclay, CEA, Centre National de Recherche en Genomique Humaine (CNRGH), Evry, France
  113. 113. Invitae, San Francisco, CA, United States
  114. 114. Unite de Recherche Clinique, Hopital Bichat, Assistance Publique-Hopitaux de Paris, Paris, France
  115. 115. Centre d’Investigation Clinique, Hopital Bichat, Assistance Publique-Hopitaux de Paris, Paris, France
  116. 116. Sorbonne Universite, INSERM Centre d’Immunologie et des Maladies Infectieuses, CIMI-Paris, Departement d’immunologie Hopital Pitie-Salpetriere, Assistance Publique-Hopitaux de Paris, Paris, France
  117. 117. Sorbonne Universite, INSERM, Institut Pierre Louis d’Epidemiologie et de Sante Publique, AP-HP, Hopital Pitie Salpetriere, Departement de Sante Publique, Unite de Recherche Clinique PSL-CFX, CIC-1901, Paris, France
  118. 118. Emergency Department, Hopital Pitie-Salpetriere, APHP-Sorbonne Universite, Paris, France
  119. 119. GRC-14 BIOFAST Sorbonn Universite, UMR INSERM 1135, CIMI, Sorbonne Universite, Paris, France
  120. 120. Department of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium
  121. 121. Laboratory of Host Defenses, NIAID, National Institutes of Health, Bethesda, MA, United States
  122. 122. Howard Hughes Medical Institute, New York, NY, United States

Source: Genome Medicine Published:2023


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. © 2023, The Author(s).
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