PHARMACOGENOMICS OF INHALED CORTICOSTEROIDS TO REDUCE COPD EXACERBATIONS

描述(申请人提供)：慢性阻塞性肺疾病(COPD)的急性加重，以呼吸困难恶化、咳嗽和排痰增加为特征，是患者令人困扰的发作，导致他们寻求医疗护理。急性加重是慢性阻塞性肺疾病发病率、死亡率和医疗支出的主要来源。吸入性皮质类固醇(ICS)通常用于重症COPD患者，已被证明可以改善症状，降低恶化风险。然而，ICS的影响在个体之间有很大的差异。这项建议的主要假设是，临床、影像和遗传因素影响个体COPD患者对ICS的反应，以防止COPD恶化。相关基因可以通过整合遗传、基因组和表观遗传信息来识别。我们建议在ICS(布地奈德、普米克)或ICS/长效β-激动剂组合(布地奈德/福莫特罗、赛必可)在以呼吸道为主的COPD患者中的临床试验中验证这一假设，该试验嵌套在COPD基因研究中，这是一项针对COPD的多中心观察性研究。具体目标1将解决这一假设，即可以在COPD患者的外周血液中识别ICS治疗12周后的基因表达和DNA甲基化差异。AIM 2将解决这样的假设，即遗传变异将影响来自AIM 1的ICS反应基因中的基因表达水平和DNA甲基化。AIM 3将解决这一假说，即临床和影像变量以及类固醇反应基因的遗传变异将影响使用ICS的COPD患者的病情恶化风险。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与生物相关的基因集上，减少多种测试顾虑，并提高我们识别ICS反应的遗传预测因子的能力，以防止COPD的急性加重。ICS反应的临床、影像和遗传预测因素将结合起来构建预测模型，朝着个性化基因组学方法在COPD症状管理方面迈出重要一步。

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.