RGD Reference Report - Functional genetic variation in NFKBIA and susceptibility to childhood asthma, bronchiolitis, and bronchopulmonary dysplasia. - Rat Genome Database

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Functional genetic variation in NFKBIA and susceptibility to childhood asthma, bronchiolitis, and bronchopulmonary dysplasia.

Authors: Ali, Salman  Hirschfeld, Aaron F  Mayer, Matthew L  Fortuno, Edgardo S  Corbett, Nathan  Kaplan, Maia  Wang, Shirley  Schneiderman, Julia  Fjell, Christopher D  Yan, Jin  Akhabir, Loubna  Aminuddin, Farzian  Marr, Nico  Lacaze-Masmonteil, Thierry  Hegele, Richard G  Becker, Allan  Chan-Yeung, Moira  Hancock, Robert E W  Kollmann, Tobias R  Daley, Denise  Sandford, Andrew J  Lavoie, Pascal M  Turvey, Stuart E 
Citation: Ali S, etal., J Immunol. 2013 Apr 15;190(8):3949-58. doi: 10.4049/jimmunol.1201015. Epub 2013 Mar 13.
RGD ID: 40902982
Pubmed: PMID:23487427   (View Abstract at PubMed)
DOI: DOI:10.4049/jimmunol.1201015   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
bronchopulmonary dysplasia exacerbatesIAGP 40902982DNA:SNPs:promoter: (rs2233406 and rs2233409) (human)RGD 
bronchopulmonary dysplasia exacerbatesISONFKBIA (Homo sapiens)40902982; 40902982DNA:SNPs:promoter: (rs2233406 and rs2233409) (human)RGD 
childhood-onset asthma exacerbatesIAGP 40902982associated with respiratory syncytial virus infectious disease and DNA:SNPs:protomer: (rs2233409) (human)RGD 
childhood-onset asthma exacerbatesISONFKBIA (Homo sapiens)40902982; 40902982associated with respiratory syncytial virus infectious disease and DNA:SNPs:protomer: (rs2233409) (human)RGD 
Viral Bronchiolitis susceptibilityIAGP 40902982associated with respiratory syncytial virus infectious disease and DNA:SNP:promoter: (rs2233406) (human)RGD 
Viral Bronchiolitis susceptibilityISONFKBIA (Homo sapiens)40902982; 40902982associated with respiratory syncytial virus infectious disease and DNA:SNP:promoter: (rs2233406) (human)RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Airway hyperresponsiveness exacerbatesIAGP 40902982associated with respiratory syncytial virus infectious disease and DNA:SNPs:protomer: (rs2233409)RGD 
Bronchiolitis susceptibilityIAGP 40902982associated with respiratory syncytial virus infectious disease and DNA:SNP:promoter: (rs2233406)RGD 
Chronic lung disease exacerbatesIAGP 40902982DNA:SNPs:promoter: (rs2233406 and rs2233409)RGD 
Severe viral infection susceptibilityIAGP 40902982associated with respiratory syncytial virus infectious disease and DNA:SNP:promoter: (rs2233406)RGD 
Objects Annotated

Genes (Rattus norvegicus)
Nfkbia  (NFKB inhibitor alpha)

Genes (Mus musculus)
Nfkbia  (nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha)

Genes (Homo sapiens)
NFKBIA  (NFKB inhibitor alpha)


Additional Information