Glucocorticoid Genes and the Developmental Origins of Asthma Susceptibility and Treatment Response

• Published in: American journal of respiratory cell and molecular biology Vol. 52; no. 5; pp. 543 - 553
• Main Authors: Sharma, Sunita, Kho, Alvin T., Chhabra, Divya, Qiu, Weiliang, Gaedigk, Roger, Vyhlidal, Carrie A., Leeder, J. Steven, Barraza-Villarreal, Albino, London, Stephanie J., Gilliland, Frank, Raby, Benjamin A., Weiss, Scott T., Tantisira, Kelan G.
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.05.2015
• Subjects: Adrenal Cortex Hormones - therapeutic use; Age; Animals; Animals, Newborn; Asthma; Asthma - drug therapy; Asthma - embryology; Asthma - genetics; Case-Control Studies; CCAAT-Enhancer-Binding Protein-delta - genetics; Databases, Genetic; Datasets; Dexamethasone - therapeutic use; Gene expression; Gene Expression Profiling - methods; Gene Expression Regulation, Developmental - drug effects; Genetic Markers; Genetic Predisposition to Disease; Hospitals; Humans; Lung - drug effects; Lung - embryology; Lung - metabolism; Medical research; Mice; Mice, Inbred C57BL; Mortality; Original Research; Phenotype; Premature birth; Principal Component Analysis; Principal components analysis; Respiratory distress syndrome; Studies; Tacrolimus Binding Proteins - genetics; Transcription Factors - genetics; Treatment Outcome; Womens health; asthma treatment; asthma; glucocorticoid genes; lung development
• ISSN: 1044-1549; 1535-4989; 1535-4989
• DOI: 10.1165/rcmb.2014-0109OC

Antenatal corticosteroids enhance lung maturation. However, the importance of glucocorticoid genes on early lung development, asthma susceptibility, and treatment response remains unknown. We investigated whether glucocorticoid genes are important during lung development and their role in asthma susceptibility and treatment response. We identified genes that were differentially expressed by corticosteroids in two of three genomic datasets: lymphoblastoid cell lines of participants in the Childhood Asthma Management Program, a glucocorticoid chromatin immunoprecipitation/RNA sequencing experiment, or a murine model; these genes made up the glucocorticoid gene set (GCGS). Using gene expression profiles from 38 human fetal lungs and C57BL/6J murine fetal lungs, we identified developmental genes that were in the top 5% of genes contributing to the top three principal components (PCs) most highly associated with post-conceptional age. Glucocorticoid genes that were enriched in this set of developmental genes were then included in the developmental glucocorticoid gene set (DGGS). We then investigated whether glucocorticoid genes are important during lung development, and their role in asthma susceptibility and treatment response. A total of 232 genes were included in the GCGS. Analysis of gene expression demonstrated that glucocorticoid genes were enriched in lung development (P = 7.02 × 10(-26)). The developmental GCGS was enriched for genes that were differentially expressed between subjects with asthma and control subjects (P = 4.26 × 10(-3)) and were enriched after treatment of subjects with asthma with inhaled corticosteroids (P < 2.72 × 10(-4)). Our results show that glucocorticoid genes are overrepresented among genes implicated in fetal lung development. These genes influence asthma susceptibility and treatment response, suggesting their involvement in the early ontogeny of asthma.