Systems biology and in vitro validation identifies family with sequence similarity 129 member A (FAM129A) as an asthma steroid response modulator
| Autor: | Scott T. Weiss, Heming Xing, Ann Chen Wu, Kelan G. Tantisira, Michael J. McGeachie, Quan Lu, Bruce W. Church, Boris Hayete, Karl Runge, Iya Khalil, George L. Clemmer, Xiaofeng Jiang |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Small interfering RNA medicine.medical_treatment Immunology Polymorphism Single Nucleotide Dexamethasone Article Steroid Cell Line 03 medical and health sciences Adrenal Cortex Hormones Nedocromil medicine Biomarkers Tumor Immunology and Allergy Humans Anti-Asthmatic Agents Budesonide Child Gene Gene knockdown business.industry Systems Biology Epithelial Cells Transfection In vitro Asthma Neoplasm Proteins 030104 developmental biology Real-time polymerase chain reaction Child Preschool Female business Transcriptome medicine.drug |
| Zdroj: | The Journal of allergy and clinical immunology. 142(5) |
| ISSN: | 1097-6825 |
| Popis: | Background Variation in response to the most commonly used class of asthma controller medication, inhaled corticosteroids, presents a serious challenge in asthma management, particularly for steroid-resistant patients with little or no response to treatment. Objective We applied a systems biology approach to primary clinical and genomic data to identify and validate genes that modulate steroid response in asthmatic children. Methods We selected 104 inhaled corticosteroid–treated asthmatic non-Hispanic white children and determined a steroid responsiveness endophenotype (SRE) using observations of 6 clinical measures over 4 years. We modeled each subject's cellular steroid response using data from a previously published study of immortalized lymphoblastoid cell lines under dexamethasone (DEX) and sham treatment. We integrated SRE with immortalized lymphoblastoid cell line DEX responses and genotypes to build a genome-scale network using the Reverse Engineering, Forward Simulation modeling framework, identifying 7 genes modulating SRE. Results Three of these genes were functionally validated by using a stable nuclear factor κ-light-chain-enhancer of activated B cells luciferase reporter in A549 human lung epithelial cells, IL-1β cytokine stimulation, and DEX treatment. By using small interfering RNA transfection, knockdown of family with sequence similarity 129 member A (FAM129A) produced a reduction in steroid treatment response ( P Conclusion 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. |
| Databáze: | OpenAIRE |
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