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

Author:

Lee Sanghun12ORCID,Zhang Yu3,Newhams Margaret4,Novak Tanya45,Thomas Paul G6,Mourani Peter M7,Hall Mark W8,Loftis Laura L9,Cvijanovich Natalie Z10,Tarquinio Keiko M11,Schwarz Adam J12,Weiss Scott L13,Thomas Neal J14,Markovitz Barry15,Cullimore Melissa L16,Sanders Ronald C17,Zinter Matt S18,Sullivan Janice E19,Halasa Natasha B20,Bembea Melania M21,Giuliano John S22,Typpo Katri V23,Nofziger Ryan A24,Shein Steven L25,Kong Michele26,Coates Bria M27,Weiss Scott T28,Lange Christoph128,Su Helen C3,Randolph Adrienne G4529ORCID,

Affiliation:

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

Abstract

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.

Funder

National Institute of Allergy and Infectious Diseases

National Institutes of Health

Division of Intramural Research

National Heart, Lung, and Blood Institute

Northwest Genomics Center

TOPMed Informatics Research Center

TOPMed Data Coordinating Center

Publisher

Oxford University Press (OUP)

Subject

Infectious Diseases,Immunology and Allergy

Reference26 articles.

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2. Severe influenza pneumonitis in children with inherited TLR3 deficiency;Lim;J Exp Med,2019

3. Infectious disease. Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency;Ciancanelli;Science,2015

4. Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency;Hernandez;J Exp Med,2018

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