PHARMACOGENOMICS OF INHALED CORTICOSTEROIDS TO REDUCE COPD EXACERBATIONS

吸入皮质类固醇减少慢性阻塞性肺病恶化的药物基因组学

基本信息

批准号：
8526228
负责人：
CRAIG P HERSH
金额：
$ 46.81万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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：
2011-09-27 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8526228
关键词：
Acute Address Adrenal Cortex Hormones Adverse effects Affect Agonist Ancillary Study Breathing Budesonide Caring Chest Chronic Obstructive Airway Disease Clinical Clinical Trials Complex Complication Coughing DNA Methylation Data Dyspnea Epigenetic Process Expenditure Gene Expression Genes Genetic Genetic Variation Genome Genomics Healthcare Hoarseness Image Individual Inhalators Lead Learning Medical Methodology Methylation Morbidity - disease rate Observational Study Oral candidiasis Outcome Patients Pharmaceutical Preparations Pharmacogenetics Pharmacogenomics Pharmacotherapy Production Pulmicort Quality of life Randomized Respiratory physiology Risk Sample Size Scanning Single Nucleotide Polymorphism Source Sputum Steroids Symptoms Testing Variant X-Ray Computed Tomography formoterol genetic association genetic variant genome wide association study genome-wide improved mortality peripheral blood pharmacogenetic testing predictive modeling prevent response risk benefit ratio symbicort symptom management trait

项目摘要

DESCRIPTION (provided by applicant): Acute exacerbations of chronic obstructive pulmonary disease (COPD), characterized by symptoms of worsening dyspnea, increased cough and sputum production, are troubling episodes for patients, leading them to seek medical care. Acute exacerbations are a major source of morbidity, mortality, and healthcare expenditure in COPD. Inhaled corticosteroids (ICS) are commonly prescribed for patients with severe COPD and have been shown to improve symptoms and reduce exacerbation risk. However, there is substantial inter- individual variation in the effects of ICS. The overarching hypothesis of this proposal is that clinical, imaging and genetic factors influence an individual COPD patient's response to ICS to prevent COPD exacerbations. The relevant genes can be identified by integrating genetic, genomic and epigenetic information. We propose to test this hypothesis in a clinical trial of ICS (budesonide, Pulmicort) or ICS/long acting beta-agonist combination (budesonide/ formoterol, Symbicort) in subjects with airway predominant COPD, nested within the COPDGene Study, a multicenter observational study of COPD. Specific Aim 1 will address the hypothesis that gene expression and DNA methylation differences in response to ICS treatment for 12 weeks can be identified in the peripheral blood of COPD patients. Aim 2 will address the hypothesis that genetic variation will influence gene expression levels and DNA methylation in the ICS-responsive genes from Aim 1. Aim 3 will address the hypothesis that clinical and imaging variables, as well as genetic variation in steroid-responsive genes, will affect exacerbation risk in COPD subjects using ICS. The integrative genomics approach we propose can limit the pharmacogenetics testing to a biologically-relevant gene set, reducing multiple testing concerns and improving our ability to identify genetic predictors of response to ICS to prevent acute exacerbations of COPD. The clinical, imaging, and genetic predictors of ICS response will be combined to construct a predictive model, making an important step towards a personalized genomics approach to COPD symptom management.

描述（由申请人提供）：慢性阻塞性肺病（COPD）急性加重，其特征是呼吸困难恶化、咳嗽和痰液增多，给患者带来困扰，导致他们寻求医疗护理。急性加重是 COPD 发病率、死亡率和医疗支出的主要来源。吸入皮质类固醇 (ICS) 通常用于治疗严重慢性阻塞性肺病 (COPD) 患者，已被证明可以改善症状并降低病情恶化风险。然而，ICS 的效果存在很大的个体差异。该提案的总体假设是，临床、影像学和遗传因素会影响个体 COPD 患者对 ICS 的反应，以预防 COPD 恶化。通过整合遗传、基因组和表观遗传信息可以识别相关基因。我们建议在气道为主的 COPD 受试者中进行 ICS（布地奈德、普米考特）或 ICS/长效 β 激动剂组合（布地奈德/福莫特罗、Symbicort）临床试验，以检验这一假设，该试验嵌套在 COPDGene 研究（一项多中心观察性研究）中慢性阻塞性肺病。具体目标 1 将解决以下假设：可以在 COPD 患者的外周血中识别 ICS 治疗 12 周后的基因表达和 DNA 甲基化差异。目标 2 将解决遗传变异将影响目标 1 中 ICS 响应基因的基因表达水平和 DNA 甲基化的假设。目标 3 将解决临床和成像变量以及类固醇响应基因中的遗传变异的假设，将影响使用 ICS 的 COPD 受试者的恶化风险。我们提出的综合基因组学方法可以将药物遗传学测试限制在生物学相关的基因组上，减少多重测试问题，并提高我们识别 ICS 反应遗传预测因子的能力，以预防 COPD 急性加重。 ICS 反应的临床、影像和遗传预测因素将被结合起来构建一个预测模型，朝着 COPD 症状管理的个性化基因组学方法迈出重要一步。