Longitudinal Phenomics and Genetics of Severe Asthma

严重哮喘的纵向表型组学和遗传学

• 批准号: 8316403
• 负责人: EUGENE ROLAND BLEECKER
• 金额: $ 66.66万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-08 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316403
• 关键词: Accident and Emergency department; Adrenal Cortex Hormones; Affect; Asthma; Biochemical; Biological Markers; Bronchodilator Agents; Bronchoscopy; Cells; Characteristics; Child; Clinical Trials; Cluster Analysis; Collaborations; Collection; DNA; Data; Development; Dose; Genes; Genetic; Genetic Polymorphism; Guidelines; Hospitals; IL4 gene; IgE; Image; Individual; Inflammation; Inflammatory; Inflammatory Response; Injectable; Letters; Liquid substance; Longitudinal Studies; Pathway interactions; Patients; Pharmacogenetics; Phenotype; Plasma; Population; Principal Investigator; Questionnaires; Recruitment Activity; Resistance; Respiratory physiology; Role; Serum; Severities; Spirometry; Sputum; Steroids; Structure; Suspension substance; Suspensions; Symptoms; Telephone; Testing; Time; Tissues; Triamcinolone Acetonide; Variant; Visit; base; cohort; eosinophil; exome; experience; follow-up; forest; genetic analysis; genetic association; genetic profiling; longitudinal analysis; lung volume; methacholine; neutrophil; novel; phenomics; pulmonary function; response

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.

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，这部分与调节支气管炎症、肺功能或影响气道结构成分的基因序列变异有关；2)一部分患者因对药物的药理学反应而发生严重哮喘。我们的第一个目标是了解纵向特征，这在使用标准和集群方法的严重哮喘的发展是重要的。在前3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；假设随访损失20%）。基线和3年的研究将包括pft、最大支气管扩张剂可逆性、支气管对甲胆碱的反应性、综合问卷调查、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。在一项亚研究中，调查性支气管镜检查将在基线和第3年进行。在给予曲安奈德注射混悬液两周后，通过评估包括肺功能、支气管反应性、诱导痰和生物标志物在内的基线表型的变化来评估诱发表型。每年对受试者进行重新评估（肺活量测定和可逆性、eNO、痰诱导和问卷调查），每六个月进行一次电话联系。每个受试者在经历病情恶化时将被要求返回进行额外的访问。除支气管镜检查和CT检查外，所有研究均在儿童中进行。我们的第二个目标是确定基线表型的遗传和生物标志物预测因子及其随时间的变化。新受试者将被分配到当前的SARP哮喘组。当总体研究完成后，将进行新的聚类分析，与当前的聚类进行比较，包括额外的生物标志物和CT成像。在集群分配中的个别变化将被纵向评估。生物标志物和遗传分析（包括罕见变异的作用）将使用集群和纵向数据进行，包括肺功能，以及诱发系统性类固醇表型的药物遗传学分析。