PHARMACOGENOMICS OF INHALED CORTICOSTEROIDS TO REDUCE COPD EXACERBATIONS

描述（由申请方提供）：慢性阻塞性肺疾病（COPD）急性加重的特征是呼吸困难加重、咳嗽和痰液产生增加，是患者的困扰事件，导致他们寻求医疗护理。急性加重是COPD发病率、死亡率和医疗费用的主要来源。吸入性糖皮质激素（ICS）通常用于重度COPD患者，已被证明可改善症状并降低加重风险。然而，ICS的作用存在很大的个体间差异。该建议的首要假设是，临床、影像学和遗传因素影响个体COPD患者对ICS的反应，以预防COPD急性加重。通过整合遗传学、基因组学和表观遗传学信息，可以鉴定相关基因。我们建议在气道为主的COPD受试者中进行ICS（布地奈德，普米克）或ICS/长效β-受体激动剂组合（布地奈德/福莫特罗，信必可）的临床试验中检验这一假设，该试验嵌套在COPD基因研究（COPD的多中心观察性研究）中。具体目标1将解决以下假设：可以在COPD患者的外周血中鉴定对ICS治疗12周的响应的基因表达和DNA甲基化差异。目的2将解决的假设，遗传变异将影响基因表达水平和DNA甲基化的ICS响应基因从目的1。目的3将阐明临床和影像学变量以及类固醇应答基因的遗传变异将影响使用ICS的COPD受试者的急性加重风险的假设。我们提出的整合基因组学方法可以将药物遗传学检测限制在生物学相关的基因集，减少多种检测问题，提高我们识别ICS反应的遗传预测因子的能力，以预防COPD急性加重。ICS反应的临床、影像学和遗传学预测因子将结合起来构建预测模型，为COPD症状管理的个性化基因组学方法迈出重要一步。

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.