Advertisement

Letter to the EditorInfectious disease Free access | 10.1172/JCI152474

Association of rare predicted loss-of-function variants of influenza-related type I IFN genes with critical COVID-19 pneumonia

Qian Zhang,1 Aurélie Cobat,1,2,3 Paul Bastard,2,3 Luigi D. Notarangelo,4,5 Helen C. Su,4,5 Laurent Abel,1,2,3 Jean-Laurent Casanova1,2,3,6,7 on behalf of COVID Human Genetic Effort (CHGE)8

1St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA.

2Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.

3University of Paris, Imagine Institute, Paris, France.

4Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID) and

5NIAID Clinical Genomics Program, NIH, Bethesda, Maryland, USA.

6Howard Hughes Medical Institute, New York, New York, USA.

7Necker Hospital for Sick Children, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France.

8CHGE is detailed in the supplemental material.

Address correspondence to: Jean-Laurent Casanova, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA. Phone: 212.327.7331; Email: casanova@rockefeller.edu.

Find articles by Zhang, Q. in: JCI | PubMed | Google Scholar |

1St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA.

2Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.

3University of Paris, Imagine Institute, Paris, France.

4Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID) and

5NIAID Clinical Genomics Program, NIH, Bethesda, Maryland, USA.

6Howard Hughes Medical Institute, New York, New York, USA.

7Necker Hospital for Sick Children, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France.

8CHGE is detailed in the supplemental material.

Address correspondence to: Jean-Laurent Casanova, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA. Phone: 212.327.7331; Email: casanova@rockefeller.edu.

Find articles by Cobat, A. in: JCI | PubMed | Google Scholar |

1St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA.

2Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.

3University of Paris, Imagine Institute, Paris, France.

4Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID) and

5NIAID Clinical Genomics Program, NIH, Bethesda, Maryland, USA.

6Howard Hughes Medical Institute, New York, New York, USA.

7Necker Hospital for Sick Children, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France.

8CHGE is detailed in the supplemental material.

Address correspondence to: Jean-Laurent Casanova, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA. Phone: 212.327.7331; Email: casanova@rockefeller.edu.

Find articles by Bastard, P. in: JCI | PubMed | Google Scholar |

1St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA.

2Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.

3University of Paris, Imagine Institute, Paris, France.

4Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID) and

5NIAID Clinical Genomics Program, NIH, Bethesda, Maryland, USA.

6Howard Hughes Medical Institute, New York, New York, USA.

7Necker Hospital for Sick Children, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France.

8CHGE is detailed in the supplemental material.

Address correspondence to: Jean-Laurent Casanova, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA. Phone: 212.327.7331; Email: casanova@rockefeller.edu.

Find articles by Notarangelo, L. in: JCI | PubMed | Google Scholar |

1St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA.

2Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.

3University of Paris, Imagine Institute, Paris, France.

4Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID) and

5NIAID Clinical Genomics Program, NIH, Bethesda, Maryland, USA.

6Howard Hughes Medical Institute, New York, New York, USA.

7Necker Hospital for Sick Children, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France.

8CHGE is detailed in the supplemental material.

Address correspondence to: Jean-Laurent Casanova, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA. Phone: 212.327.7331; Email: casanova@rockefeller.edu.

Find articles by Su, H. in: JCI | PubMed | Google Scholar |

1St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA.

2Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.

3University of Paris, Imagine Institute, Paris, France.

4Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID) and

5NIAID Clinical Genomics Program, NIH, Bethesda, Maryland, USA.

6Howard Hughes Medical Institute, New York, New York, USA.

7Necker Hospital for Sick Children, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France.

8CHGE is detailed in the supplemental material.

Address correspondence to: Jean-Laurent Casanova, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA. Phone: 212.327.7331; Email: casanova@rockefeller.edu.

Find articles by Abel, L. in: JCI | PubMed | Google Scholar |

1St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA.

2Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.

3University of Paris, Imagine Institute, Paris, France.

4Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID) and

5NIAID Clinical Genomics Program, NIH, Bethesda, Maryland, USA.

6Howard Hughes Medical Institute, New York, New York, USA.

7Necker Hospital for Sick Children, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France.

8CHGE is detailed in the supplemental material.

Address correspondence to: Jean-Laurent Casanova, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA. Phone: 212.327.7331; Email: casanova@rockefeller.edu.

Find articles by Casanova, J. in: JCI | PubMed | Google Scholar |

1St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA.

2Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.

3University of Paris, Imagine Institute, Paris, France.

4Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID) and

5NIAID Clinical Genomics Program, NIH, Bethesda, Maryland, USA.

6Howard Hughes Medical Institute, New York, New York, USA.

7Necker Hospital for Sick Children, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France.

8CHGE is detailed in the supplemental material.

Address correspondence to: Jean-Laurent Casanova, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA. Phone: 212.327.7331; Email: casanova@rockefeller.edu.

Published June 22, 2021 - More info

Published in Volume 131, Issue 15 on August 2, 2021
J Clin Invest. 2021;131(15):e152474. https://doi.org/10.1172/JCI152474.
© 2021 American Society for Clinical Investigation
Published June 22, 2021 - Version history
View PDF

Related articles:

Rare loss-of-function variants in type I IFN immunity genes are not associated with severe COVID-19
Gundula Povysil, … , David B. Goldstein, Krzysztof Kiryluk
Gundula Povysil, … , David B. Goldstein, Krzysztof Kiryluk
Concise Communication Genetics Infectious disease

Rare loss-of-function variants in type I IFN immunity genes are not associated with severe COVID-19

Abstract

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,864 COVID-19 cases (713 with severe and 1,151 with mild disease) and 15,033 ancestry-matched population controls across 4 independent COVID-19 biobanks. We tested whether rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only 1 rare pLOF mutation across these genes among 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We found no evidence of association of rare LOF variants in the 13 candidate genes with severe COVID-19 outcomes.

Authors

Gundula Povysil, Guillaume Butler-Laporte, Ning Shang, Chen Wang, Atlas Khan, Manal Alaamery, Tomoko Nakanishi, Sirui Zhou, Vincenzo Forgetta, Robert J.M. Eveleigh, Mathieu Bourgey, Naveed Aziz, Steven J.M. Jones, Bartha Knoppers, Stephen W. Scherer, Lisa J. Strug, Pierre Lepage, Jiannis Ragoussis, Guillaume Bourque, Jahad Alghamdi, Nora Aljawini, Nour Albes, Hani M. Al-Afghani, Bader Alghamdi, Mansour S. Almutairi, Ebrahim Sabri Mahmoud, Leen Abu-Safieh, Hadeel El Bardisy, Fawz S. Al Harthi, Abdulraheem Alshareef, Bandar Ali Suliman, Saleh A. Alqahtani, Abdulaziz Almalik, May M. Alrashed, Salam Massadeh, Vincent Mooser, Mark Lathrop, Mohamed Fawzy, Yaseen M. Arabi, Hamdi Mbarek, Chadi Saad, Wadha Al-Muftah, Junghyun Jung, Serghei Mangul, Radja Badji, Asma Al Thani, Said I. Ismail, Ali G. Gharavi, Malak S. Abedalthagafi, J. Brent Richards, David B. Goldstein, Krzysztof Kiryluk

×
Association of rare predicted loss-of-function variants of influenza-related type I IFN genes with critical COVID-19 pneumonia. Reply.
Gundula Povysil, … , David B. Goldstein, Krzysztof Kiryluk
Gundula Povysil, … , David B. Goldstein, Krzysztof Kiryluk
Letter to the Editor Infectious disease

Association of rare predicted loss-of-function variants of influenza-related type I IFN genes with critical COVID-19 pneumonia. Reply.

Abstract

Authors

Gundula Povysil, Guillaume Butler-Laporte, Ali G. Gharavi, J. Brent Richards, David B. Goldstein, Krzysztof Kiryluk

×
To the Editor:

Povysil et al. report that “rare loss-of-function variants in type I IFN immunity genes are not associated with severe COVID-19” (1). We disagree with the authors’ interpretation of our data (2) and their own for 6 reasons: (i) Only predicted loss-of-function LOF (pLOF) variants are relevant for comparison between the 2 studies, because, unlike our group, Povysil et al. did not test variants experimentally. The relevant proportion in our data is therefore not 23/659, or 3.5%, but 9/659, or 1.36%; whereas theirs is 1/713, or 0.14%. (ii) Our definitions of “severe/critical” disease are different: we defined critical disease as having severity grades 6–10 according to the WHO scale (3), whereas Povysil et al. restricted their recruitment to grades 7–10 (i.e., excluding patients on high-flow oxygen, who were considered in our study). Their cohort of “mild” cases may therefore have included severe COVID-19 cases (grade 6), such as perhaps the TLR3 pLOF carrier designated as having mild disease. (iii) The controls in the work by Povysil et al. comprised individuals from the general population, without depletion of COVID-19 genetic risk factors, whereas we included paucisymptomatic and asymptomatic infected subjects (grades 1–3) as controls. Consequently, the power computation shown in their Figure 1 is based on an incorrect hypothesis about the odds ratio, which would be expected to be lower when using general population controls (as they did) than when using paucisymptomatic and asymptomatic infected individuals (as we did). (iv) The ethnic origin of the patients differs between the 2 studies: 58% of our 659 patients (and 8 of our 9 pLOF carriers) were European, versus only 10% of their 713 patients with severe disease (and the pLOF carrier was East Asian). (v) Age is a key factor neglected in their comparison: our sample was much younger (mean age, 51.8 years) than theirs (mean, 65.9 years), and 7 of our 9 pLOF carriers were younger than 60 years. We performed a comparison stratified by age (<60 versus ≥60 years), and no significant difference in pLOF proportion was found between the 2 studies, even ignoring the only patient carrying a pLOF they identified (of unknown age): 7/458 in our sample versus 0/192 in their sample (P = 0.11, Fisher’s exact test) for patients younger than 60 years, and 2/201 versus 0/521 (P = 0.07) for patients at least 60 years old. (vi) Finally, and crucially, the authors did not exclude patients with autoantibodies against type I IFN, which account for at least 10% of critical cases; these autoantibodies are much more frequent in patients older than 60 years, particularly men (4).

Supplemental material

View Supplemental data

Footnotes

Conflict of interest: The authors have declared that no conflict of interest exists.

Reference information: J Clin Invest. 2021;131(15):e152474. https://doi.org/10.1172/JCI152474.

See the related article at Rare loss-of-function variants in type I IFN immunity genes are not associated with severe COVID-19.

See the related reference at Association of rare predicted loss-of-function variants of influenza-related type I IFN genes with critical COVID-19 pneumonia. Reply..

References
  1. Povysil G, et al. Rare loss-of-function variants in type I IFN immunity genes are not associated with severe COVID-19. J Clin Invest. 2021;131(14):e147834.
    View this article via: JCI CrossRef PubMed Google Scholar
  2. Zhang Q, et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science. 2020;370(6515):eabd4570.
    View this article via: CrossRef PubMed Google Scholar
  3. WHO Working Group on the Clinical Characterisation and Management of COVID-19 infection. A minimal common outcome measure set for COVID-19 clinical research. Lancet Infect Dis. 2020;20(8):e192–e197.
    View this article via: CrossRef PubMed Google Scholar
  4. Bastard P, et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science. 2020;370(6515):eabd4585.
    View this article via: CrossRef PubMed Google Scholar
Version history
  • Version 1 (June 22, 2021): In-Press Preview
  • Version 2 (August 2, 2021): Electronic publication
Advertisement
Advertisement