title: Functional genetic variation in NFKBIA and susceptibility to childhood asthma, bronchiolitis, and bronchopulmonary dysplasia.
abstract: Respiratory diseases are the most frequent chronic illnesses in babies and children. Although a vigorous innate immune system is critical for maintaining lung health, a balanced response is essential to minimize damaging inflammation. We investigated the functional and clinical impact of human genetic variants in the promoter of NFKBIA, which encodes IκBα, the major negative regulator of NF-κB. In this study, we quantified the functional impact of NFKBIA promoter polymorphisms (rs3138053, rs2233406, and rs2233409) on promoter-driven protein expression, allele-specific and total NFKBIA mRNA expression, IκBα protein expression, and TLR responsiveness; mapped innate immune regulatory networks active during respiratory syncytial virus infection, asthma, and bronchopulmonary dysplasia; and genotyped and analyzed independent cohorts of children with respiratory syncytial virus infection, asthma, and bronchopulmonary dysplasia. Genetic variants in the promoter of NFKBIA influenced NFKBIA gene expression, IκBα protein expression, and TLR-mediated inflammatory responses. Using a systems biology approach, we demonstrated that NFKBIA/IκBα is a central hub in transcriptional responses of prevalent childhood lung diseases, including respiratory syncytial virus infection, asthma, and bronchopulmonary dysplasia. Finally, by examining independent pediatric lung disease cohorts, we established that this immunologically relevant genetic variation in the promoter of NFKBIA is associated with differential susceptibility to severe bronchiolitis following infection with respiratory syncytial virus, airway hyperresponsiveness, and severe bronchopulmonary dysplasia. These data highlight the importance of negative innate immune regulators, such as NFKBIA, in pediatric lung disease and begin to unravel common aspects in the genetic predisposition to bronchopulmonary dysplasia, bronchiolitis, and childhood asthma.
authors.affiliation: Department of Pediatrics, British Columbia Children's Hospital and Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia V6H 3V4, Canada.
authors.forename: Salman
authors.initials: S
authors.lastname: Ali
authors.forename: Aaron F
authors.initials: AF
authors.lastname: Hirschfeld
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Mayer
authors.forename: Edgardo S
authors.initials: ES
authors.lastname: Fortuno
authors.forename: Nathan
authors.initials: N
authors.lastname: Corbett
authors.forename: Maia
authors.initials: M
authors.lastname: Kaplan
authors.forename: Shirley
authors.initials: S
authors.lastname: Wang
authors.forename: Julia
authors.initials: J
authors.lastname: Schneiderman
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Fjell
authors.forename: Jin
authors.initials: J
authors.lastname: Yan
authors.forename: Loubna
authors.initials: L
authors.lastname: Akhabir
authors.forename: Farzian
authors.initials: F
authors.lastname: Aminuddin
authors.forename: Nico
authors.initials: N
authors.lastname: Marr
authors.forename: Thierry
authors.initials: T
authors.lastname: Lacaze-Masmonteil
authors.forename: Richard G
authors.initials: RG
authors.lastname: Hegele
authors.forename: Allan
authors.initials: A
authors.lastname: Becker
authors.forename: Moira
authors.initials: M
authors.lastname: Chan-Yeung
authors.forename: Robert E W
authors.initials: RE
authors.lastname: Hancock
authors.forename: Tobias R
authors.initials: TR
authors.lastname: Kollmann
authors.forename: Denise
authors.initials: D
authors.lastname: Daley
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sandford
authors.forename: Pascal M
authors.initials: PM
authors.lastname: Lavoie
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Turvey
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology*; D001988:Bronchiolitis / Q000235:genetics / Q000276:immunology* / Q000821:virology; D001997:Bronchopulmonary Dysplasia / Q000235:genetics / Q000276:immunology* / Q000821:virology; D016466:CHO Cells; D002648:Child; D002675:Child, Preschool; D006224:Cricetinae; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000276:immunology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D052002:NF-kappa B p50 Subunit / Q000235:genetics* / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D012136:Respiratory Syncytial Viruses / Q000276:immunology
chemical_list: D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human