Michael J McGeachie1, George L Clemmer2, Boris Hayete3, Heming Xing4, Karl Runge3, Ann Chen Wu5, Xiaofeng Jiang6, Quan Lu6, Bruce Church3, Iya Khalil3, Kelan Tantisira7, Scott Weiss7. 1. Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Mass; Department of Medicine, Harvard Medical School, Boston, Mass. Electronic address: michael.mcgeachie@channing.harvard.edu. 2. Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Mass. 3. GNS Healthcare, Cambridge, Mass. 4. Novartis Institute for Biomedical Research, Cambridge, Mass. 5. Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Mass; Department of Medicine, Harvard Medical School, Boston, Mass; Precision Medicine Translational Research (PROMoTeR) Center, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Mass. 6. Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Mass. 7. Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Mass; Department of Medicine, Harvard Medical School, Boston, Mass.
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 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.
RCT Entities:
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 A549human 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 asthmasteroid responsiveness and that FAM129A modulates steroid responsiveness in lung epithelial cells.
Authors: Heming Xing; Paul D McDonagh; Jadwiga Bienkowska; Tanya Cashorali; Karl Runge; Robert E Miller; Dave Decaprio; Bruce Church; Ronenn Roubenoff; Iya G Khalil; John Carulli Journal: PLoS Comput Biol Date: 2011-03-10 Impact factor: 4.475
Authors: Elizabeth M King; Joanna E Chivers; Christopher F Rider; Anne Minnich; Mark A Giembycz; Robert Newton Journal: PLoS One Date: 2013-01-14 Impact factor: 3.240
Authors: Jiang Li; Ronald Panganiban; Alvin T Kho; Michael J McGeachie; Leanna Farnam; Robert P Chase; Scott T Weiss; Quan Lu; Kelan G Tantisira Journal: Am J Respir Crit Care Med Date: 2020-07-01 Impact factor: 21.405