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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：
9058588
负责人：
EUGENE ROLAND BLEECKER
金额：
$ 62.34万
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 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9058588
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 Markers Genetic Polymorphism Genetic study Guidelines Hospitals IL4 gene IgE Individual Inflammation Inflammatory Inflammatory Response Injectable Letters Liquid substance Longitudinal Studies Pathway interactions Pharmacogenetics Phenotype Plasma Population Questionnaires Recruitment Activity Resistance Respiratory physiology Role Serum Severities Spirometry Sputum Steroids Structure Suspension substance Suspensions Telephone Testing Time Tissues Triamcinolone Acetonide Variant Visit X-Ray Computed Tomography base cohort early onset eosinophil exome sequencing experience follow-up forest genetic analysis genetic association genetic profiling longitudinal analysis lung volume methacholine neutrophil novel patient subsets persistent symptom phenomics pulmonary function rare variant 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.

描述（由申请方提供）：我们假设1）重度哮喘的一个重要原因是炎症反应改变，其与调节支气管炎症、肺功能或影响气道结构组分的基因序列变异部分相关，2）一部分患者由于对药物的药物遗传学反应而发生重度哮喘。我们的第一个目的是了解纵向特征，这是重要的发展严重哮喘使用标准和集群的方法。在前3年的每一年，我们将招募和描述96例受试者（60%患有重度哮喘，25%为儿童;假设20%失访）。基线和3年研究将包括PFT、最大支气管扩张剂可逆性、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和总血清IgE水平、诱导痰、eNO和CT成像。在子研究中，将在基线和第3年进行研究性支气管镜检查。在曲安奈德注射混悬液给药后2周，通过评价基线表型（包括肺功能、支气管反应性、诱导痰和生物标志物）的变化，评估诱发表型。每年对受试者进行重新评估（肺功能测定和可逆性、eNO、痰液诱导和问卷调查），每6个月进行一次额外的电话联系。当每例受试者发生急性加重时，将要求其返回接受额外访视。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SARP哮喘组。当研究总人群时，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。将纵向评估聚类分配的个体变化。将使用聚类和纵向数据（包括肺功能）以及诱发全身类固醇表型的药物遗传学分析进行生物标志物和遗传分析（包括罕见变异体的作用）。