Longitudinal Phenomics and Genetics of Severe Asthma

严重哮喘的纵向表型组学和遗传学

基本信息

批准号：
8175592
负责人：
EUGENE ROLAND BLEECKER
金额：
$ 58.26万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-08 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8175592
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

项目摘要

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，该反应与调节支气管炎症、肺功能或影响气道结构成分的基因序列变异部分相关，2) 一个子集的患者由于对药物的药物遗传学反应而发展为严重哮喘。我们的首要目标是使用标准方法和集群方法了解在严重哮喘发展中重要的纵向特征。在前 3 年中，我们每年都会招募 96 名受试者并对其进行表征（60% 患有严重哮喘，25% 是儿童；假设有 20% 的患者失访）。基线和 3 年研究将包括 PFT、最大支气管扩张可逆性、支气管对乙酰甲胆碱的反应性、综合问卷、血液嗜酸性粒细胞、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 年进行调查性支气管镜检查。在给予曲安奈德注射混悬液两周后，将通过评估基线表型的变化（包括肺功能、支气管反应性、诱导痰和生物标志物）来评估诱发表型。每年将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），并每六个月进行一次额外的电话联系。每个受试者在病情恶化时都将被要求返回进行额外的访视。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及其随时间变化的遗传和生物标志物预测因子。新受试者将被分配到当前的 SARP 哮喘集群。研究完总人口后，将进行新的聚类分析，以与当前聚类进行比较，包括额外的生物标志物和 CT 成像。集群分配中的个体变化将纵向评估。将使用包括肺功能在内的聚类和纵向数据以及诱发的全身类固醇表型的药物遗传学分析来进行生物标志物和遗传分析（包括罕见变异的作用）。相关性：该提案的目的有两个：首先，使用标准和新颖的分析方法了解严重哮喘发展中重要的纵向特征；其次，确定基线表型及其随时间变化的遗传和生物标志物预测因子。