Acute exacerbations of chronic obstructive pulmonary disease (COPD), characterized by symptoms of worsening dyspnea, increased cough and sputum production, are troubling episodes for patients, leading them to seek medical care. Acute exacerbations are a major source of morbidity, mortality, and healthcare expenditure in COPD. Inhaled corticosteroids (ICS) are commonly prescribed for patients with severe COPD and have been shown to improve symptoms and reduce exacerbation risk. However, there is substantial inter- individual variation in the effects of ICS. The overarching hypothesis of this proposal is that clinical, imaging and genetic factors influence an individual COPD patient's response to ICS to prevent COPD exacerbations. The relevant genes can be identified by integrating genetic, genomic and epigenetic information. We propose to test this hypothesis in a clinical trial of ICS (budesonide, Pulmicort) or ICS/long acting beta-agonist combination (budesonide/ formoterol, Symbicort) in subjects with airway predominant COPD, nested within the COPDGene Study, a multicenter observational study of COPD.
Specific Aim 1 will address the hypothesis that gene expression and DNA methylation differences in response to ICS treatment for 12 weeks can be identified in the peripheral blood of COPD patients.
Aim 2 will address the hypothesis that genetic variation will influence gene expression levels and DNA methylation in the ICS-responsive genes from Aim 1.
Aim 3 will address the hypothesis that clinical and imaging variables, as well as genetic variation in steroid-responsive genes, will affect exacerbation risk in COPD subjects using ICS. The integrative genomics approach we propose can limit the pharmacogenetics testing to a biologically-relevant gene set, reducing multiple testing concerns and improving our ability to identify genetic predictors of response to ICS to prevent acute exacerbations of COPD. The clinical, imaging, and genetic predictors of ICS response will be combined to construct a predictive model, making an important step towards a personalized genomics approach to COPD symptom management.
The Pharmacogenomics of Inhaled Corticosteroids to Reduce Chronic Obstructive Pulmonary Disease (COPD) Exacerbations study will allow us to find genes that affect an individual's response to steroid inhalers to prevent acute exacerbations of COPD. The information we learn may eventually lead to a more personalized approach to the treatment of COPD patients.
|Hardin, M; Cho, M H; McDonald, M-L et al. (2016) A genome-wide analysis of the response to inhaled Î²2-agonists in chronic obstructive pulmonary disease. Pharmacogenomics J 16:326-35|
|Busch, Robert; Han, MeiLan K; Bowler, Russell P et al. (2016) Risk factors for COPD exacerbations in inhaled medication users: the COPDGene study biannual longitudinal follow-up prospective cohort. BMC Pulm Med 16:28|
|Hayden, Lystra P; Cho, Michael H; McDonald, Merry-Lynn N et al. (2016) Susceptibility to Childhood Pneumonia: A Genome-Wide Analysis. Am J Respir Cell Mol Biol :|
|Park, Seoung Ju; Make, Barry; Hersh, Craig P et al. (2015) Significance of Medication History at the Time of Entry into the COPDGene Study: Relationship with Exacerbation and CT Metrics. COPD 12:366-73|
|Morrow, Jarrett D; Qiu, Weiliang; Chhabra, Divya et al. (2015) Identifying a gene expression signature of frequent COPD exacerbations in peripheral blood using network methods. BMC Med Genomics 8:1|
|Castaldi, Peter J; Cho, Michael H; Zhou, Xiaobo et al. (2015) Genetic control of gene expression at novel and established chronic obstructive pulmonary disease loci. Hum Mol Genet 24:1200-10|
|Hayden, Lystra P; Hobbs, Brian D; Cohen, Robyn T et al. (2015) Childhood pneumonia increases risk for chronic obstructive pulmonary disease: the COPDGene study. Respir Res 16:115|
|Hobbs, Brian D; Foreman, Marilyn G; Bowler, Russell et al. (2014) Pneumothorax risk factors in smokers with and without chronic obstructive pulmonary disease. Ann Am Thorac Soc 11:1387-94|
|McDonald, Merry-Lynn N; Cho, Michael H; SÃ¸rheim, Inga-Cecilie et al. (2014) Common genetic variants associated with resting oxygenation in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 51:678-87|
|Hobbs, Brian D; Hersh, Craig P (2014) Integrative genomics of chronic obstructive pulmonary disease. Biochem Biophys Res Commun 452:276-86|
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