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: Salman Ali, Aaron F Hirschfeld, Matthew L Mayer, Edgardo S Fortuno 3rd, Nathan Corbett, Maia Kaplan, Shirley Wang, Julia Schneiderman, Christopher D Fjell, Jin Yan, Loubna Akhabir, Farzian Aminuddin, Nico Marr, Thierry Lacaze-Masmonteil, Richard G Hegele, Allan Becker, Moira Chan-Yeung, Robert E W Hancock, Tobias R Kollmann, Denise Daley, Andrew J Sandford, Pascal M Lavoie, Stuart E Turvey
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 190 Issue 8 Pg. 3949-58 (Apr 15 2013) ISSN: 1550-6606 [Electronic] United States
• PMID: 23487427 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• NF-kappa B p50 Subunit
• NFKB1 protein, human

Topics

• Animals
• Asthma (genetics, immunology)
• Bronchiolitis (genetics, immunology, virology)
• Bronchopulmonary Dysplasia (genetics, immunology, virology)
• CHO Cells
• Child
• Child, Preschool
• Cricetinae
• Female
• Genetic Predisposition to Disease
• Genetic Variation (immunology)
• Humans
• Infant
• Infant, Newborn
• NF-kappa B p50 Subunit (genetics, physiology)
• Polymorphism, Single Nucleotide
• Promoter Regions, Genetic (genetics)
• Respiratory Syncytial Viruses (immunology)