@article{976524234f65412686f79a1cc8561184,
title = "DDX58 Is Associated With Susceptibility to Severe Influenza Virus Infection in Children and Adolescents",
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{\textquoteright} 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",
author = "{Pediatric Intensive Care Influenza (PICFlu)} and {Trans-Omics for Precision Medicine (TOPMed)} and {the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI)} and Sanghun Lee and Yu Zhang and Margaret Newhams and Tanya Novak and Thomas, {Paul G.} and Mourani, {Peter M.} and Hall, {Mark W.} and Loftis, {Laura L.} and Cvijanovich, {Natalie Z.} and Tarquinio, {Keiko M.} and Schwarz, {Adam J.} and Weiss, {Scott L.} and Thomas, {Neal J.} and Barry Markovitz and Cullimore, {Melissa L.} and Sanders, {Ronald C.} and Zinter, {Matt S.} and Sullivan, {Janice E.} and Halasa, {Natasha B.} and Bembea, {Melania M.} and GiulianoJr, {John S.} and Typpo, {Katri V.} and Nofziger, {Ryan A.} and Shein, {Steven L.} and Michele Kong and Coates, {Bria M.} and Weiss, {Scott T.} and Christoph Lange and Su, {Helen C.} and Randolph, {Adrienne G.}",
note = "Funding Information: We thank Michael Ciancanelli and Jean-Laurent Casanova for helpful discussions. This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) (AI154470 to A. R., P. T., and C. L.; AI084011 to A. R.; Division of Intramural Research to Y. Z. and H. C. S.; and 2U01HG008685 and P01HL132825 to S. T. W.). Molecular data for the TOPMed program were supported by the National Heart, Lung, and Blood Institute (NHLBI), NIH. Genome sequencing for “NHLBI TOPMed: Genetic Epidemiology of Asthma in Costa Rica” (phs000988.v4.p1) and “NHLBI TOPMed: Childhood Asthma Management Program (CAMP)” (phs001726.v1.p1) was performed at the Northwest Genomics Center (HHSN268201600032I, 3R37 HL066289-13S1). Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract number HHSN268201800002I). Core support including phenotype harmonization, data management, sample-identity quality control, and general program coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract number HHSN26 8201800001I). Publisher Copyright: {\textcopyright} The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved.",
year = "2022",
month = dec,
day = "1",
doi = "10.1093/infdis/jiac350",
language = "English (US)",
volume = "226",
pages = "2030--2036",
journal = "Journal of Infectious Diseases",
issn = "0022-1899",
publisher = "Oxford University Press",
number = "11",
}