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.
|Marozkina, Nadzeya V; Wang, Xin-Qun; Stsiapura, Vitali et al. (2015) Phenotype of asthmatics with increased airway S-nitrosoglutathione reductase activity. Eur Respir J 45:87-97|
|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|
|Ortega, V E (2014) Pharmacogenetics of beta2 adrenergic receptor agonists in asthma management. Clin Genet 86:12-20|
|Meyers, Deborah A; Bleecker, Eugene R; Holloway, John W et al. (2014) Asthma genetics and personalised medicine. Lancet Respir Med 2:405-15|
|Moore, Wendy C; Bleecker, Eugene R (2014) Asthma heterogeneity and severity-why is comprehensive phenotyping important? Lancet Respir Med 2:10-1|
|Ortega, Victor E; Hawkins, Gregory A; Moore, Wendy C et al. (2014) Effect of rare variants in ADRB2 on risk of severe exacerbations and symptom control during longacting ? agonist treatment in a multiethnic asthma population: a genetic study. Lancet Respir Med 2:204-13|
|Ortega, Victor E; Meyers, Deborah A (2014) Implications of population structure and ancestry on asthma genetic studies. Curr Opin Allergy Clin Immunol 14:381-9|
|Hastie, Annette T; Moore, Wendy C; Li, Huashi et al. (2013) Biomarker surrogates do not accurately predict sputum eosinophil and neutrophil percentages in asthmatic subjects. J Allergy Clin Immunol 132:72-80|
|Sah, Pravin K; Gerald Teague, W; Demuth, Karen A et al. (2013) Poor asthma control in obese children may be overestimated because of enhanced perception of dyspnea. J Allergy Clin Immunol Pract 1:39-45|
|Fitzpatrick, Anne M; Baena-Cagnani, Carlos E; Bacharier, Leonard B (2012) Severe asthma in childhood: recent advances in phenotyping and pathogenesis. Curr Opin Allergy Clin Immunol 12:193-201|