We hypothesize that 1) an important cause of severe asthma is altered inflammatory responses that are partially related to sequence variants in genes that regulate bronchial inflammation, pulmonary function or affect structural components in the airways and 2) a subset of patients develops severe asthma because of pharmacogenetic responses to pharmacologic agents.
Our first aim i s to understand the longitudinal characteristics that are important in the development of severe asthma using both standard and cluster approaches. For each of the first 3 years, we will recruit and characterize 96 subjects (60 % with severe asthma, 25% children;assuming 20% loss to follow up). Baseline and 3 year studies will include PFTs, maximum bronchodilator reversibility, bronchial responsiveness to methacholine, comprehensive questionnaires, blood for eosinophils, neutrophils, DNA and total serum IgE levels, induced sputum, eNO and CT imaging. In a substudy, investigative bronchoscopy will be performed at baseline and year 3. An evoked phenotype will be assessed two weeks after administration of triamcinolne acetonide injectable suspension by evaluating changes in baseline phenotypes including lung function, bronchial responsiveness, induced sputum and biomarkers. Subjects will be reassessed yearly (spirometry and reversibility, eNO, sputum induction and questionnaires) with additional telephone contact every six months. Each subject will be asked to return for an additional visit when they are experiencing an exacerbation. All studies with the exception of bronchoscopy and CT imaging will be performed in children.
Our second aim i s to determine genetic and biomarker predictors of baseline phenotypes and their change over time. New subjects will be assigned to a current SARP asthma cluster. When the total population has been studied, a new cluster analysis will be performed for comparison with the current clusters, including additional biomarkers and CT imaging. Individual changes in cluster assignment will be assessed longitudinally. Biomarker and genetic analysis (including the role of rare variants) will be performed using the clusters and longitudinal data including lung function, as well as pharmacogenetic analysis of the evoked systemic steroid phenotype.
The purpose of this proposal is twofold: First, to understand the longitudinal characteristics that are important in the development of severe asthma using both standard and novel analytical approaches and second, to determine genetic and biomarker predictors of baseline phenotypes and their change overtime.
|Teague, W Gerald; Phillips, Brenda R; Fahy, John V et al. (2018) Baseline Features of the Severe Asthma Research Program (SARP III) Cohort: Differences with Age. J Allergy Clin Immunol Pract 6:545-554.e4|
|Ash, Samuel Y; Rahaghi, Farbod N; Come, Carolyn E et al. (2018) Pruning of the Pulmonary Vasculature in Asthma. The Severe Asthma Research Program (SARP) Cohort. Am J Respir Crit Care Med 198:39-50|
|Wong-McGrath, Kelly; Denlinger, Loren C; Bleecker, Eugene R et al. (2018) Internet-Based Monitoring in the Severe Asthma Research Program Identifies a Subgroup of Patients With Labile Asthma Control. Chest 153:378-386|
|Hastie, A T; Steele, C; Dunaway, C W et al. (2018) Complex association patterns for inflammatory mediators in induced sputum from subjects with asthma. Clin Exp Allergy 48:787-797|
|DeBoer, Mark D; Phillips, Brenda R; Mauger, David T et al. (2018) Effects of endogenous sex hormones on lung function and symptom control in adolescents with asthma. BMC Pulm Med 18:58|
|Hawkins, Gregory A; Mora, Ana L (2017) FAM13A, A Fatty Acid Oxidation Switch in Mitochondria. Friend or Foe in Chronic Obstructive Pulmonary Disease Pathogenesis? Am J Respir Cell Mol Biol 56:689-691|
|Johnston, Henry Richard; Hu, Yi-Juan; Gao, Jingjing et al. (2017) Identifying tagging SNPs for African specific genetic variation from the African Diaspora Genome. Sci Rep 7:46398|
|Ricklefs, Isabell; Barkas, Ioanna; Duvall, Melody G et al. (2017) ALX receptor ligands define a biochemical endotype for severe asthma. JCI Insight 2:|
|Phipatanakul, Wanda; Mauger, David T; Sorkness, Ronald L et al. (2017) Effects of Age and Disease Severity on Systemic Corticosteroid Responses in Asthma. Am J Respir Crit Care Med 195:1439-1448|
|Duvall, Melody G; Barnig, Cindy; Cernadas, Manuela et al. (2017) Natural killer cell-mediated inflammation resolution is disabled in severe asthma. Sci Immunol 2:|
Showing the most recent 10 out of 28 publications