. 2022 Nov 28;226(11):2030-2036.

doi: 10.1093/infdis/jiac350.

DDX58 Is Associated With Susceptibility to Severe Influenza Virus Infection in Children and Adolescents

Sanghun Lee^{1

2}, Yu Zhang³, Margaret Newhams⁴, Tanya Novak^{4

5}, Paul G Thomas⁶, Peter M Mourani⁷, Mark W Hall⁸, Laura L Loftis⁹, Natalie Z Cvijanovich¹⁰, Keiko M Tarquinio¹¹, Adam J Schwarz¹², Scott L Weiss¹³, Neal J Thomas¹⁴, Barry Markovitz¹⁵, Melissa L Cullimore¹⁶, Ronald C Sanders¹⁷, Matt S Zinter¹⁸, Janice E Sullivan¹⁹, Natasha B Halasa²⁰, Melania M Bembea²¹, John S Giuliano²², Katri V Typpo²³, Ryan A Nofziger²⁴, Steven L Shein²⁵, Michele Kong²⁶, Bria M Coates²⁷, Scott T Weiss²⁸, Christoph Lange^{1

28}, Helen C Su³, Adrienne G Randolph^{4

5

29}; Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Pediatric Intensive Care Influenza (PICFlu) Investigators and the Trans-Omics for Precision Medicine (TOPMed) Investigators

Affiliations

¹ Department of Biostatistics, T. H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.
² Department of Medical Consilience, Graduate School, Dankook University, Yongin-si, South Korea.
³ Laboratory of Clinical Immunology and Microbiology, Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
⁴ Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
⁵ Department of Anesthesia, Harvard Medical School, Boston, Massachusetts, USA.
⁶ Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
⁷ Section of Critical Care Medicine, Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Research Institute, Little Rock, Arkansas, USA.
⁸ Division of Critical Care Medicine, Department of Pediatrics, Nationwide Children's Hospital, Columbus, Ohio, USA.
⁹ Section of Critical Care Medicine, Department of Pediatrics, Texas Children's Hospital, Houston, Texas, USA.
¹⁰ Division of Critical Care Medicine, UCSF Benioff Children's Hospital Oakland, Oakland, California, USA.
¹¹ Division of Critical Care Medicine, Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
¹² Department of Pediatrics, Children's Hospital of Orange County, Orange, California, USA.
¹³ Division of Critical Care, Department of Anesthesiology and Critical Care, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
¹⁴ Department of Pediatrics, Penn State Hershey Children's Hospital, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
¹⁵ Department of Anesthesiology Critical Care Medicine, Children's Hospital Los Angeles, Los Angeles, California, USA.
¹⁶ Division of Pediatric Critical Care, Department of Pediatrics, University of Nebraska Medical Center, Omaha, Nebraska, USA.
¹⁷ Section of Pediatric Critical Care, Department of Pediatrics, Arkansas Children's Hospital, Little Rock, Arkansas, USA.
¹⁸ Divisions of Critical Care Medicine and Allergy, Immunology, and Bone Marrow Transplant, Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA.
¹⁹ Division of Pediatric Critical Care, University of Louisville School of Medicine and Norton Children's Hospital, Louisville, Kentucky, USA.
²⁰ Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
²¹ Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²² Division of Critical Care, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA.
²³ Department of Pediatrics, Steele Children's Research Center, University of Arizona, Tucson, Arizona, USA.
²⁴ Division of Critical Care Medicine, Department of Pediatrics, Akron Children's Hospital, Akron, Ohio, USA.
²⁵ Division of Pediatric Critical Care Medicine, Rainbow Babies and Children's Hospital, Cleveland, Ohio, USA.
²⁶ Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
²⁷ Division of Critical Care Medicine, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
²⁸ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
²⁹ Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.

PMID: 35986912
PMCID: PMC10205622
DOI: 10.1093/infdis/jiac350

DDX58 Is Associated With Susceptibility to Severe Influenza Virus Infection in Children and Adolescents

Sanghun Lee et al. J Infect Dis. 2022.

. 2022 Nov 28;226(11):2030-2036.

doi: 10.1093/infdis/jiac350.

Authors

Affiliations

¹ Department of Biostatistics, T. H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.
² Department of Medical Consilience, Graduate School, Dankook University, Yongin-si, South Korea.
³ Laboratory of Clinical Immunology and Microbiology, Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
⁴ Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
⁵ Department of Anesthesia, Harvard Medical School, Boston, Massachusetts, USA.
⁶ Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
⁷ Section of Critical Care Medicine, Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Research Institute, Little Rock, Arkansas, USA.
⁸ Division of Critical Care Medicine, Department of Pediatrics, Nationwide Children's Hospital, Columbus, Ohio, USA.
⁹ Section of Critical Care Medicine, Department of Pediatrics, Texas Children's Hospital, Houston, Texas, USA.
¹⁰ Division of Critical Care Medicine, UCSF Benioff Children's Hospital Oakland, Oakland, California, USA.
¹¹ Division of Critical Care Medicine, Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
¹² Department of Pediatrics, Children's Hospital of Orange County, Orange, California, USA.
¹³ Division of Critical Care, Department of Anesthesiology and Critical Care, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
¹⁴ Department of Pediatrics, Penn State Hershey Children's Hospital, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
¹⁵ Department of Anesthesiology Critical Care Medicine, Children's Hospital Los Angeles, Los Angeles, California, USA.
¹⁶ Division of Pediatric Critical Care, Department of Pediatrics, University of Nebraska Medical Center, Omaha, Nebraska, USA.
¹⁷ Section of Pediatric Critical Care, Department of Pediatrics, Arkansas Children's Hospital, Little Rock, Arkansas, USA.
¹⁸ Divisions of Critical Care Medicine and Allergy, Immunology, and Bone Marrow Transplant, Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA.
¹⁹ Division of Pediatric Critical Care, University of Louisville School of Medicine and Norton Children's Hospital, Louisville, Kentucky, USA.
²⁰ Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
²¹ Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²² Division of Critical Care, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA.
²³ Department of Pediatrics, Steele Children's Research Center, University of Arizona, Tucson, Arizona, USA.
²⁴ Division of Critical Care Medicine, Department of Pediatrics, Akron Children's Hospital, Akron, Ohio, USA.
²⁵ Division of Pediatric Critical Care Medicine, Rainbow Babies and Children's Hospital, Cleveland, Ohio, USA.
²⁶ Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
²⁷ Division of Critical Care Medicine, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
²⁸ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
²⁹ Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.

PMID: 35986912
PMCID: PMC10205622
DOI: 10.1093/infdis/jiac350

Abstract

Background: Seasonal influenza virus infection causes a range of disease severity, including lower respiratory tract infection with respiratory failure. We evaluated the association of common variants in interferon (IFN) regulatory genes with susceptibility to critical influenza infection in children.

Methods: We performed targeted sequencing of 69 influenza-associated candidate genes in 348 children from 24 US centers admitted to the intensive care unit with influenza infection and lacking risk factors for severe influenza infection (PICFlu cohort, 59.4% male). As controls, whole genome sequencing from 675 children with asthma (CAMP cohort, 62.5% male) was compared. We assessed functional relevance using PICFlu whole blood gene expression levels for the gene and calculated IFN gene signature score.

Results: Common variants in DDX58, encoding the retinoic acid-inducible gene I (RIG-I) receptor, demonstrated association above or around the Bonferroni-corrected threshold (synonymous variant rs3205166; intronic variant rs4487862). The intronic single-nucleotide polymorphism rs4487862 minor allele was associated with decreased DDX58 expression and IFN signature (P < .05 and P = .0009, respectively) which provided evidence supporting the genetic variants' impact on RIG-I and IFN immunity.

Conclusions: We provide evidence associating common gene variants in DDX58 with susceptibility to severe influenza infection in children. RIG-I may be essential for preventing life-threatening influenza-associated disease.

Keywords: DDX58; RIG-I receptor; host genetics; pediatric influenza; susceptibility.

PubMed Disclaimer

Conflict of interest statement

Potential conflicts of interest. A. G. R. reports receiving reagents to her institution from Illumina Inc for work outside of this project. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

**Figure 1.**
Principal components analysis plot showing adjustment for race (A), quantile–quantile plot (B), and Manhattan plot (C) for generalized logistic regression of 2 cohorts (PICFlu vs CAMP) adjusting for age, sex, and 10 principal components of genetic ancestry under the additive model. The grey dotted line in the Manhattan plot shows a Bonferroni-corrected threshold of .05 (P = 3.90 × 10⁻⁵), which only synonymous variant DDX58 rs3205166 exceeds, with intronic DDX58 rs4487862 the dot below it (P = .0016). Abbreviations: AFR, African; CAMP, Childhood Asthma Management Program; EUR, European; LAT, Latino; PC, principal component; PCA, principal components analysis; PICFlu, Pediatric Intensive Care Influenza.

**Figure 2.**
*DDX58* (retinoic acid–inducible gene I) expression level (A) and interferon gene signature (ISG) score (B) according to genotyping of the *DDX58* common variants rs3205166 and rs4487862. **P < .01, ***P < .001; ns, not significant.

See this image and copyright information in PMC

References

1. Centers for Disease Control and Prevention . Disease burden of flu. https://www.cdc.gov/flu/about/burden/index.html. Accessed 28 July 2022.
1. Fineberg HV. Pandemic preparedness and response—lessons from the H1N1 influenza of 2009. N Engl J Med 2014; 370:1335–42. - PubMed
1. Lim HK, Huang SXL, Chen J, et al. Severe influenza pneumonitis in children with inherited TLR3 deficiency. J Exp Med 2019; 216:2038–56. - PMC - PubMed
1. Ciancanelli MJ, Huang SX, Luthra P, et al. Infectious disease. Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency. Science 2015; 348:448–53. - PMC - PubMed
1. Hernandez N, Melki I, Jing H, et al. Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency. J Exp Med 2018; 215:2567–85. - PMC - PubMed

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DDX58 Is Associated With Susceptibility to Severe Influenza Virus Infection in Children and Adolescents

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DDX58 Is Associated With Susceptibility to Severe Influenza Virus Infection in Children and Adolescents

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Conflict of interest statement

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