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Letter to the EditorInfectious disease Free access | 10.1172/JCI152475

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

Gundula Povysil,1 Guillaume Butler-Laporte,2,3 Ali G. Gharavi,4,5 J. Brent Richards,2,3,6,7 David B. Goldstein,1,8 and Krzysztof Kiryluk4,5

1Institute for Genomic Medicine, Columbia University, New York, New York, USA.

2Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.

3Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada.

4Department of Medicine and

5Institute for Genomic Medicine, Columbia University, New York, New York, USA.

6Department of Human Genetics, McGill University, Montreal, Canada.

7Department of Twin Research, King’s College London, London, United Kingdom.

8Department of Genetics and Development, Columbia University, New York, New York, USA.

Address correspondence to: J. Brent Richards, 3755 Côte Sainte Catherine, Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2. Phone: 514.340.8222 ext. 24362; Email: brent.richards@mcgill.ca. Or to: David B. Goldstein, 701 West 168th Street, New York, New York 10032, USA. Phone: 212.305.0923; Email: dg2875@cumc.columbia.edu. Or to: Krzysztof Kiryluk, 1150 St. Nicholas Ave, New York, New York 10032, USA. Phone: 212.851.4926; Email: kk473@columbia.edu.

Find articles by Povysil, G. in: JCI | PubMed | Google Scholar |

1Institute for Genomic Medicine, Columbia University, New York, New York, USA.

2Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.

3Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada.

4Department of Medicine and

5Institute for Genomic Medicine, Columbia University, New York, New York, USA.

6Department of Human Genetics, McGill University, Montreal, Canada.

7Department of Twin Research, King’s College London, London, United Kingdom.

8Department of Genetics and Development, Columbia University, New York, New York, USA.

Address correspondence to: J. Brent Richards, 3755 Côte Sainte Catherine, Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2. Phone: 514.340.8222 ext. 24362; Email: brent.richards@mcgill.ca. Or to: David B. Goldstein, 701 West 168th Street, New York, New York 10032, USA. Phone: 212.305.0923; Email: dg2875@cumc.columbia.edu. Or to: Krzysztof Kiryluk, 1150 St. Nicholas Ave, New York, New York 10032, USA. Phone: 212.851.4926; Email: kk473@columbia.edu.

Find articles by Butler-Laporte, G. in: JCI | PubMed | Google Scholar |

1Institute for Genomic Medicine, Columbia University, New York, New York, USA.

2Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.

3Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada.

4Department of Medicine and

5Institute for Genomic Medicine, Columbia University, New York, New York, USA.

6Department of Human Genetics, McGill University, Montreal, Canada.

7Department of Twin Research, King’s College London, London, United Kingdom.

8Department of Genetics and Development, Columbia University, New York, New York, USA.

Address correspondence to: J. Brent Richards, 3755 Côte Sainte Catherine, Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2. Phone: 514.340.8222 ext. 24362; Email: brent.richards@mcgill.ca. Or to: David B. Goldstein, 701 West 168th Street, New York, New York 10032, USA. Phone: 212.305.0923; Email: dg2875@cumc.columbia.edu. Or to: Krzysztof Kiryluk, 1150 St. Nicholas Ave, New York, New York 10032, USA. Phone: 212.851.4926; Email: kk473@columbia.edu.

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

1Institute for Genomic Medicine, Columbia University, New York, New York, USA.

2Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.

3Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada.

4Department of Medicine and

5Institute for Genomic Medicine, Columbia University, New York, New York, USA.

6Department of Human Genetics, McGill University, Montreal, Canada.

7Department of Twin Research, King’s College London, London, United Kingdom.

8Department of Genetics and Development, Columbia University, New York, New York, USA.

Address correspondence to: J. Brent Richards, 3755 Côte Sainte Catherine, Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2. Phone: 514.340.8222 ext. 24362; Email: brent.richards@mcgill.ca. Or to: David B. Goldstein, 701 West 168th Street, New York, New York 10032, USA. Phone: 212.305.0923; Email: dg2875@cumc.columbia.edu. Or to: Krzysztof Kiryluk, 1150 St. Nicholas Ave, New York, New York 10032, USA. Phone: 212.851.4926; Email: kk473@columbia.edu.

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

1Institute for Genomic Medicine, Columbia University, New York, New York, USA.

2Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.

3Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada.

4Department of Medicine and

5Institute for Genomic Medicine, Columbia University, New York, New York, USA.

6Department of Human Genetics, McGill University, Montreal, Canada.

7Department of Twin Research, King’s College London, London, United Kingdom.

8Department of Genetics and Development, Columbia University, New York, New York, USA.

Address correspondence to: J. Brent Richards, 3755 Côte Sainte Catherine, Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2. Phone: 514.340.8222 ext. 24362; Email: brent.richards@mcgill.ca. Or to: David B. Goldstein, 701 West 168th Street, New York, New York 10032, USA. Phone: 212.305.0923; Email: dg2875@cumc.columbia.edu. Or to: Krzysztof Kiryluk, 1150 St. Nicholas Ave, New York, New York 10032, USA. Phone: 212.851.4926; Email: kk473@columbia.edu.

Find articles by Goldstein, D. in: JCI | PubMed | Google Scholar

1Institute for Genomic Medicine, Columbia University, New York, New York, USA.

2Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.

3Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada.

4Department of Medicine and

5Institute for Genomic Medicine, Columbia University, New York, New York, USA.

6Department of Human Genetics, McGill University, Montreal, Canada.

7Department of Twin Research, King’s College London, London, United Kingdom.

8Department of Genetics and Development, Columbia University, New York, New York, USA.

Address correspondence to: J. Brent Richards, 3755 Côte Sainte Catherine, Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2. Phone: 514.340.8222 ext. 24362; Email: brent.richards@mcgill.ca. Or to: David B. Goldstein, 701 West 168th Street, New York, New York 10032, USA. Phone: 212.305.0923; Email: dg2875@cumc.columbia.edu. Or to: Krzysztof Kiryluk, 1150 St. Nicholas Ave, New York, New York 10032, USA. Phone: 212.851.4926; Email: kk473@columbia.edu.

Find articles by Kiryluk, K. in: JCI | PubMed | Google Scholar |

Published June 22, 2021 - More info

Published in Volume 131, Issue 15 on August 2, 2021
J Clin Invest. 2021;131(15):e152475. https://doi.org/10.1172/JCI152475.
© 2021 American Society for Clinical Investigation
Published June 22, 2021 - Version history
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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

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Association of rare predicted loss-of-function variants of influenza-related type I IFN genes with critical COVID-19 pneumonia
Qian Zhang, … , Jean-Laurent Casanova, on behalf of COVID Human Genetic Effort (CHGE)
Qian Zhang, … , Jean-Laurent Casanova, on behalf of COVID Human Genetic Effort (CHGE)
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

Abstract

Authors

Qian Zhang, Aurélie Cobat, Paul Bastard, Luigi D. Notarangelo, Helen C. Su, Laurent Abel, Jean-Laurent Casanova, on behalf of COVID Human Genetic Effort (CHGE)

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The authors reply:

We appreciate the interest of Dr. Zhang and colleagues in our article (1, 2). The main difference between our study and that by Zhang et al. (3) is that we assessed all rare predicted loss-of-function variants (pLOFs) meeting the same criteria in the case and control groups, which is a well-established paradigm in the field (4). In contrast, Zhang et al. included specific variants that were experimentally confirmed only in cases, but not in controls, precluding a valid case-control comparison.

We matched patients as closely as possible to those in the previous study, and the inclusion of more-severe cases (WHO grades 7–10) should only strengthen the signal against population controls. The use of population controls is standard in such settings and has minimal impact on power, because only a small proportion of individuals exposed to SARS-CoV-2 develop severe disease (5). Additionally, for the pLOF model, we report adequate power even for an odds ratio of 5.5, which is considerably lower than the one reported by Zhang et al. We tested the same dominant model as Zhang et al., even though LOF variants in these genes have only been reported to cause disease under recessive inheritance (6).

We have serious concerns about ancestry as a confounding factor in the analysis by Zhang et al., in which the pLOF carriers were mostly European, but functionally validated missense variants were found in individuals of various nationalities from Asia, Europe, Latin America, and the Middle East. Because the rates of pLOFs vary considerably across populations, adjustment for only 3 principal components of ancestry in rare-variant association tests of multiethnic cohorts does not provide adequate control for population structure.

While we noted that age differences may contribute to the discrepancies between the 2 studies, Zhang et al. do not discuss the role of age in the interpretation of their results, stating, “Inborn errors of TLR3- and IRF7-dependent type I IFN immunity at eight loci were found in as many as 23 patients (3.5%) of various ages (17–77 years) and ancestries (various nationalities from Asia, Europe, Latin America, and the Middle East) and in patients of both sexes.” We also note that the patients with autoantibodies were not excluded from the primary analysis by Zhang et al.; this was done only in the post hoc analysis.

Most importantly, our negative findings are in full agreement with the recently published independent sequencing study of 586,157 individuals, including 20,952 with COVID-19 (4928 hospitalized and 1304 with severe disease requiring ventilation or resulting in death; ref. 7). There were no significant associations with any of the 13 candidate genes examined either individually or in aggregate, or when comparisons included all hospitalized cases or only the most severe cases. Indeed, none of the associations showed even marginal significance. Therefore, consistent with our study, these findings do not support substantial contributions of inborn errors in type I IFN immunity to COVID-19 severity.

These negative results underscore the importance of proper study design, selection of appropriate genetic models, adequate control for genetic ancestry, and adherence to unbiased methods for genetic discovery rather than focusing only on a candidate biological pathway.

Footnotes

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

Reference information: J Clin Invest. 2021;131(15):e152475. https://doi.org/10.1172/JCI152475.

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 letter to the editor at Association of rare predicted loss-of-function variants of influenza-related type I IFN genes with critical COVID-19 pneumonia.

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.
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  2. Zhang Q, et al. Association of rare predicted loss-of-function variants of influenza-related type I IFN genes with critical COVID-19 pneumonia. J Clin Invest. 2021;131(15):e152474.
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    View this article via: PubMed Google Scholar
Version history
  • Version 1 (June 22, 2021): In-Press Preview
  • Version 2 (August 2, 2021): Electronic publication
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