Systems biology and in vitro validation identifies family with sequence similarity 129 member A (FAM129A) as an asthma steroid response modulator - 06/11/18
, George L. Clemmer, SM a, ∗, Boris Hayete, PhD c, Heming Xing, PhD d, Karl Runge, PhD c, Ann Chen Wu, MD, MPH a, b, f, Xiaofeng Jiang, PhD e, Quan Lu, PhD e, Bruce Church, PhD c, Iya Khalil, PhD c, Kelan Tantisira, MD a, b, Scott Weiss, MD, SM a, bAbstract |
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.
Le texte complet de cet article est disponible en PDF.Key words : Inhaled corticosteroids, steroid response endophenotype, genomics, FAM129A, Reverse Engineering, Forward Simulation modeling, systems biology
Abbreviations used : CAMP, DEX, EDARADD, FAF1, FAM129A, FAM174B, FICD, GLCCI1, GWAS, ICS, LCL, MDS, NF-κB, QC, REFS, siRNA, SNP, SRE, YY1
Plan
| Supported by grants U01 HL65899 and R01 HL092197. M.J.M. is supported by a grant from the Parker B. Francis Foundation. K.T. is supported by grants R01 HL127332 and R01 HL129935. A.C.W. is supported by grant R01 HD085993. Q.L. is supported by grant R01 HL114769. |
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| Disclosure of potential conflict of interest: M. J. McGeachie's institute received grants from National Institutes of Health (NIH) and the Parker B. Francis Foundation for this work and grants from the NIH for other works. G. L. Clemmer's institute received a grant from the NIH/National Heart, Lung, and Blood Institute for this work. B. Hayete's, K. Runge's, and B. Church's institute (GNS) has received a project fee from Harvard Medical School for conducting this analyses. A. C. Wu's institute received grants R01 HD090019-01A1 (National Human Genome Research Institute (NHGRI/NIH), 1602-34331 (Patient-Centers Outcomes Research Institute [PCORI]), 1R01HD085993-01 (Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD/NIH), 1R21HG008510-01 (NHGRI/NIH), and 1R01HS022093-01A1 (Agency for Healthcare Research and Quality [AHRQ]/NIH) for this work. Q. Lu's institute received grants R01HL114769 (NIH) and AAF 15-0097 (American Asthma Foundation) for this work and grant R01 HL139496-01 (NIH [pending]) for other works; the institute received US Patent no. 9,737,480 (unrelated to Journal of Allergy and Clinical Immunology publication); and US patent application no. 14/929,177 (unrelated to Journal of Allergy and Clinical Immunology publication). I. Khalil is employed by GNS Healthcare. K. Tantisira's institution received a grant from the NIH for this work and other works. S. Weiss has received payment to GNS to use their software to perform network analysis used. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 142 - N° 5
P. 1479 - novembre 2018 Retour au numéro
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