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

J Allergy Clin Immunol. 2018 Nov;142(5):1479-1488.e12. doi: 10.1016/j.jaci.2017.11.059. Epub 2018 Mar 2.


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 < .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.

Keywords: FAM129A; Inhaled corticosteroids; Reverse Engineering, Forward Simulation modeling; genomics; steroid response endophenotype; systems biology.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex Hormones / therapeutic use*
  • Anti-Asthmatic Agents / therapeutic use*
  • Asthma / drug therapy*
  • Asthma / genetics*
  • Biomarkers, Tumor / genetics*
  • Budesonide / therapeutic use
  • Cell Line
  • Child
  • Child, Preschool
  • Dexamethasone / pharmacology
  • Epithelial Cells / metabolism
  • Female
  • Humans
  • Male
  • Nedocromil / therapeutic use
  • Neoplasm Proteins / genetics*
  • Polymorphism, Single Nucleotide
  • Systems Biology
  • Transcriptome


  • Adrenal Cortex Hormones
  • Anti-Asthmatic Agents
  • Biomarkers, Tumor
  • NIBAN1 protein, human
  • Neoplasm Proteins
  • Nedocromil
  • Budesonide
  • Dexamethasone