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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Cooperative Clinical Research--Cooperative Agreements (U10)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-K (M2))
Program Officer
Noel, Patricia
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wake Forest University Health Sciences
Other Health Professions
Schools of Medicine
United States
Zip Code
Denlinger, Loren C; Phillips, Brenda R; Ramratnam, Sima et al. (2016) Inflammatory and Co-Morbid Features of Patients with Severe Asthma and Frequent Exacerbations. Am J Respir Crit Care Med :
Peters, Michael C; McGrath, Kelly Wong; Hawkins, Gregory A et al. (2016) Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts. Lancet Respir Med 4:574-84
Kessler, Michael D; Yerges-Armstrong, Laura; Taub, Margaret A et al. (2016) Challenges and disparities in the application of personalized genomic medicine to populations with African ancestry. Nat Commun 7:12521
Fitzpatrick, Anne M (2016) Severe Asthma in Children: Lessons Learned and Future Directions. J Allergy Clin Immunol Pract 4:11-9; quiz 20-1
Mathias, Rasika Ann; Taub, Margaret A; Gignoux, Christopher R et al. (2016) A continuum of admixture in the Western Hemisphere revealed by the African Diaspora genome. Nat Commun 7:12522
Robinson, Mac B; Deshpande, Deepak A; Chou, Jeffery et al. (2015) IL-6 trans-signaling increases expression of airways disease genes in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 309:L129-38
Ortega, Victor E; Kumar, Rajesh (2015) The Effect of Ancestry and Genetic Variation on Lung Function Predictions: What Is ""Normal"" Lung Function in Diverse Human Populations? Curr Allergy Asthma Rep 15:16
Ortega, Victor E; Meyers, Deborah A; Bleecker, Eugene R (2015) Asthma pharmacogenetics and the development of genetic profiles for personalized medicine. Pharmgenomics Pers Med 8:9-22
Ortega, Victor E; Meyers, Deborah A (2014) Pharmacogenetics: implications of race and ethnicity on defining genetic profiles for personalized medicine. J Allergy Clin Immunol 133:16-26
Moore, Wendy C; Bleecker, Eugene R (2014) Asthma heterogeneity and severity-why is comprehensive phenotyping important? Lancet Respir Med 2:10-1

Showing the most recent 10 out of 17 publications