Systems biology and in vitro validation identifies family with sequence similarity 129 member A (FAM129A) as an asthma steroid response modulator.
Systems biology and in vitro validation identifies family with sequence similarity 129 member A (FAM129A) as an asthma steroid response modulator.
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DOI：
10.1016/j.jaci.2017.11.059
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发表时间：
2018-11
期刊：
影响因子：
--
通讯作者：
Weiss S
中科院分区：
文献类型：
--
作者：
McGeachie MJ;Clemmer GL;Hayete B;Xing H;Runge K;Wu AC;Jiang X;Lu Q;Church B;Khalil I;Tantisira K;Weiss S
对最常用的一类哮喘控制药物（吸入皮质类固醇（ICS））的反应差异，对哮喘管理提出了严重的挑战，特别是对治疗反应很少或没有反应的类固醇抵抗患者。我们应用系统生物学方法对主要临床和基因组数据进行分析，以确定和验证哮喘儿童中调节类固醇反应的基因。我们选择了104名接受ics治疗的非西班牙裔白人哮喘儿童，通过4年6项临床指标的观察，确定了类固醇反应性内表型（SRE）。我们利用先前发表的一项永生化淋巴母细胞样细胞系（LCL）在地塞米松（DEX）和假治疗下的研究数据，模拟了每个受试者的细胞类固醇反应。我们将SRE与LCL DEX反应和基因型相结合，利用逆向工程，正向模拟（REFS）建模框架构建了基因组规模的网络，确定了7个调节SRE的基因。其中三个基因通过稳定的nf - κ b Luc报告基因在A549人肺上皮细胞、il - 1β细胞因子刺激和地塞米松治疗中进行功能验证。使用siRNA转染，敲低家族序列相似129成员A （FAM129A）可降低类固醇治疗反应（p<0.001）。通过这种基于系统的方法，我们已经证明FAM129A与临床哮喘类固醇反应性的变化有关，并且FAM129A调节肺上皮细胞的类固醇反应性。
Variation in response to the most commonly used class of asthma controller medication, inhaled corticosteroids (ICS), presents a serious challenge in asthma management, particularly for steroid-resistant patients who display little or no response to treatment. We applied a systems-biology approach to primary clinical and genomic data to identify and validate genes that modulate steroid response in children with asthma. We selected 104 ICS-treated asthmatic non-Hispanic white children and determined a Steroid Responsiveness Endophenotype (SRE) using observations of six clinical measures over four years. We modeled each subject’s cellular steroid response using data from a previously published study of immortalized lymphoblastoid cell lines (LCL) under dexamethasone (DEX) and sham treatment. We integrated SRE with LCL DEX response and genotypes to build a genome-scale network using the Reverse Engineering, Forward Simulation (REFS) modeling framework, identifying seven genes modulating SRE. Three of these genes were functionally validated using a stable NFκB Luc reporter in A549 Human lung epithelial cells, IL1β cytokine stimulation, and dexamethasone treatment. Using siRNA transfection, knockdown of Family With Sequence Similarity 129 Member A (FAM129A) produced a reduction in steroid treatment response (p<0.001). With this systems-based approach, we have shown that FAM129A is associated with variation in clinical asthma steroid responsiveness and that FAM129A modulates steroid responsiveness in lung epithelial cells.
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