Systems biology and in vitro validation identifies FAM129A as asthma steroid response modulator.

View Abstract

BACKGROUND

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.

OBJECTIVE

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.

METHODS

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.

RESULTS

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).

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.

Investigators
Abbreviation
J. Allergy Clin. Immunol.
Publication Date
2018-01-30
Pubmed ID
29410046
Medium
Print-Electronic
Full Title
Systems biology and in vitro validation identifies FAM129A as asthma steroid response modulator.
Authors
McGeachie MJ, Clemmer GL, Hayete B, Xing H, Runge K, Wu AC, Jiang X, Lu Q, Church B, Khalil I, Tantisira K, Weiss S