Longitudinal Phenomics and Genetics of Severe Asthma

描述(由申请人提供)：我们假设1)严重哮喘的一个重要原因是炎症反应的改变，这些炎症反应部分与调节支气管炎、肺功能或影响呼吸道结构成分的基因的序列变异有关，2)部分患者由于对药物的药物遗传反应而患上严重哮喘。我们的第一个目标是使用标准和分组方法来了解在严重哮喘的发展中重要的纵向特征。在前三年的每一年，我们将招募96名受试者并对其进行特征描述(60%患有严重哮喘，25%为儿童；假设失去20%的随访)。基线和3年的研究将包括PFTs、最大支气管扩张剂可逆性、支气管对乙酰胆碱的反应性、综合问卷调查、血中嗜酸性粒细胞、中性粒细胞、DNA和血清总IgE水平、诱导痰、eNO和CT成像。在一项子研究中，将在基线和第3年进行调查支气管镜检查。在服用曲安奈德注射混悬液两周后，将通过评估基线表型的变化来评估诱发表型，包括肺功能、支气管反应性、诱导痰和生物标志物。受试者将每年重新评估(肺活量和可逆性、ENO、痰诱导和问卷调查)，每六个月增加一次电话联系。当每个受试者病情恶化时，他们将被要求再来一次探视。除支气管镜检查和CT成像外，所有研究都将在儿童中进行。我们的第二个目标是确定基线表型的遗传和生物标记物预测因子及其随时间的变化。新的受试者将被分配到目前的SARP哮喘集群。当研究了总体人口后，将进行新的聚类分析，以与当前的聚类进行比较，包括额外的生物标记物和CT成像。将对分组分配的个别变化进行纵向评估。生物标记物和遗传分析(包括罕见变异的作用)将使用包括肺功能在内的集群和纵向数据进行，以及对诱发的全身类固醇表型进行药物遗传学分析。 相关性：这项建议的目的有两个：第一，使用标准和新的分析方法了解在重症哮喘发展中重要的纵向特征，第二，确定基线表型的遗传和生物标志物预测因子及其随时间的变化。

DESCRIPTION (provided by applicant): 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 is 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 is 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. 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.