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Systems biology and in vitro validation identifies family with sequence similarity 129 member A (FAM129A) as an asthma steroid response modulator.

ABSTRACT: 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 ?-light-chain-enhancer of activated B cells luciferase reporter in A549 human lung epithelial cells, IL-1? 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 < .001). 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.

SUBMITTER: McGeachie MJ

PROVIDER: S-EPMC6111005 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Systems biology and in vitro validation identifies family with sequence similarity 129 member A (FAM129A) as an asthma steroid response modulator.

McGeachie Michael J MJ Clemmer George L GL Hayete Boris B Xing Heming H Runge Karl K Wu Ann Chen AC Jiang Xiaofeng X Lu Quan Q Church Bruce B Khalil Iya I Tantisira Kelan K Weiss Scott S

The Journal of allergy and clinical immunology 20180302 5

<h4>Background</h4>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.<h4>Objective</h4>We applied a systems biology approach to primary clinical and genomic data to identify and validate genes that modulate steroid response in asthmatic children.<h4>Methods</h4>We selected 104 inhaled corticosteroid-tr ...[more]

PMID: 29410046

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Dataset Information

Systems biology and in vitro validation identifies family with sequence similarity 129 member A (FAM129A) as an asthma steroid response modulator.

Publications

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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