Functional Genetic Variation in NFKBIA and Susceptibility to Childhood Asthma, Bronchiolitis, and Bronchopulmonary Dysplasia
Functional Genetic Variation in NFKBIA and Susceptibility to Childhood Asthma, Bronchiolitis, and Bronchopulmonary Dysplasia
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DOI：
10.4049/jimmunol.1201015
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发表时间：
2013-04-15
影响因子：
4.4
通讯作者：
Turvey, Stuart E.
中科院分区：
文献类型：
--
作者：
Ali, Salman;Hirschfeld, Aaron F.;Turvey, Stuart E.
呼吸道疾病是婴儿和儿童最常见的慢性疾病。虽然强有力的先天免疫系统对于维持肺部健康至关重要，但平衡的反应对于最大限度地减少破坏性炎症至关重要。我们研究了NF-κ BIA启动子中人类遗传变异的功能和临床影响，NF-κ BIA编码NF-κ B的主要负调节因子I κ B α。在这项研究中，我们量化了NFKBIA启动子多态性的功能影响，（rs3138053、rs 2233406和rs 2233409）对启动子驱动的蛋白质表达、等位基因特异性和总NFKBIA mRNA表达、I κ B α蛋白表达和TLR反应性的影响;绘制了在呼吸道合胞病毒感染、哮喘和支气管肺发育不良期间活跃的先天免疫调节网络;对呼吸道合胞病毒感染、哮喘和支气管肺发育不良的儿童进行基因分型和分析。NFKBIA启动子中的遗传变异影响NFKBIA基因表达、I κ B α蛋白表达和TLR介导的炎症反应。使用系统生物学方法，我们证明了NF κ BIA/I κ B α是流行性儿童肺部疾病（包括呼吸道合胞病毒感染、哮喘和支气管肺发育不良）转录反应的中心枢纽。最后，通过检查独立的儿科肺病队列，我们确定NFKBIA启动子中的这种免疫相关遗传变异与呼吸道合胞病毒感染后严重细支气管炎、气道高反应性和严重支气管肺发育不良的不同易感性相关。这些数据突出了阴性先天免疫调节因子（如NFKBIA）在儿科肺部疾病中的重要性，并开始揭示了支气管肺发育不良、细支气管炎和儿童哮喘遗传易感性的共同方面。免疫学杂志，2013，190：3949-3958。
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 I kappa B alpha, the major negative regulator of NF-kappa B. 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, I kappa B alpha 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, I kappa B alpha protein expression, and TLR-mediated inflammatory responses. Using a systems biology approach, we demonstrated that NFKBIA/I kappa B alpha 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. The Journal of Immunology, 2013, 190: 3949-3958.