Clinical Implications, Genomics, and Transcriptions of Mucus Plugging in Smokers

项目摘要/摘要 气流阻塞是慢性阻塞性肺疾病(COPD)的重要病理生理特征。 慢性阻塞性肺病影响着大约2890万人，是美国第三大死因。 尽管吸烟是慢性阻塞性肺疾病的主要危险因素，但也有证据表明遗传易感性。 单基因综合征--α-1抗胰蛋白酶缺乏和皮肤松弛--有肺气肿，一种慢性阻塞性肺疾病 表型，作为其表现的一部分。导致气流的未被充分研究的病理生理特征 COPD的梗阻是粘液功能障碍。香烟烟雾引起的粘液功能障碍导致增加 粘液的产生和清除减少，导致其在呼吸道中积聚和堵塞的形成， 这又会导致气流受阻。肺组织研究表明，通过以下方式阻断小气道 粘液渗出与疾病严重程度和死亡率有关，强调了粘液的临床相关性。 功能障碍。目前对慢性阻塞性肺疾病粘液功能障碍的临床和遗传学研究的主要局限性是 他们依靠自我报告的数据，如慢性咳嗽、痰和肺组织来反映这一点。 反常现象。 在这项建议中，我们将在胸部计算机断层扫描(CT)上直观地识别粘液堵塞并对其进行评分 登记到COPD基因的受试者，对COPD的纵向评估以确定预测性替代终点 军事人员早期肺癌的点数(日食)和检测(DECAMP)-2项研究-大型 患有和不患有慢性阻塞性肺疾病的吸烟者队列。在目标1中，我们将在第一阶段、第二阶段和第三阶段CT中进行视觉评分 COPD基因研究扫描。然后，我们将确定与10年CT变化相关的因素- 确定粘液堵塞以及这种影像特征与急性呼吸道疾病的关系 插曲和死亡。在目标2中，我们将在所有基线的eclipse CT扫描中对粘液堵塞进行评分，并使用 来自Aim 1的COPD基因得分以执行全基因组关联研究，以确定共同和 与CT确定的粘液堵塞相关的罕见遗传变异。我们将利用全基因组基因分型， 以及用于基因发现的全基因组测序数据。然后我们将测试这些关联 CT确定的粘液堵塞与常见和罕见的遗传变异之间的Meta分析 COPDgene和ECLIPSE队列。最后，在目标3中，我们将对吸烟者的CT扫描进行粘液堵塞评分 参加了DeCamp-2的学习。将对收集的支气管和鼻腔进行转录分析 上皮细胞识别基于成像的粘液堵塞的基因表达差异。我们相信这一点 该项目将增加对粘液功能障碍的临床和遗传方面的了解，这是COPD的一个明显差距，并将 提供有效的影像评估，可用于临床和流行病学调查。

Project Summary/Abstract Airflow obstruction is a defining pathophysiologic feature of chronic obstructive pulmonary disease (COPD). COPD affects approximately 28.9 million people and is the 3rd leading cause of death in the United States. Although the main risk factor for COPD is cigarette smoking, there is evidence of genetic susceptibility as well. Monogenic syndromes —Alpha-1 antitrypsin deficiency and cutis laxa— have emphysema, a COPD phenotype, as part of their manifestations. An understudied pathophysiologic feature leading to airflow obstruction in COPD is mucus dysfunction. Cigarette smoke-induced mucus dysfunction results in increased production of and reduced clearance of mucus leading to its accumulation in the airways and plug formation, which in turn leads to airflow obstruction. Lung tissue studies demonstrated that occlusion of small airways by mucous exudates are related to disease severity and mortality, underscoring the clinical relevance of mucus dysfunction. The main limitation of current clinical and genetic studies of mucus dysfunction in COPD is that they have relied on self-reported data such as chronic cough and phlegm and lung tissue to reflect this abnormality. In this proposal we will visually identify and score mucus plugging on chest computed tomography (CT) from subjects enrolled into the COPDGene, Evaluation of COPD Longitudinally to Identify Predictive Surrogate End- points (ECLIPSE) and Detection of Early Lung Cancer Among Military Personnel (DECAMP)-2 studies —large cohorts of smokers with and without COPD. In Aim 1, we will perform a visual scoring in phases 1, 2 and 3 CT scans of the COPDGene Study. We will then determine the factors associated with 10-yr changes in CT- identified mucus plugging as well as the associations of this imaging feature to acute respiratory disease episodes and death. In Aim 2, we will score mucus plugging in all baseline ECLIPSE CT scans and use the scores of COPDGene from Aim 1 to perform genome-wide association studies to determine the common and rare genetic variants related to CT-identified mucus plugging. We will utilize genome-wide genotyping, imputation, and whole-genome sequencing data for gene discovery. We will then test the associations between CT-identified mucus plugging and common and rare genetic variants using meta-analysis in COPDGene and ECLIPSE cohorts. Finally, in Aim 3 we will score mucus plugging on CT scans from smokers enrolled into DECAMP-2 Study. The transcriptomic analysis will be performed in collected bronchial and nasal epithelial cells to identify gene expression differences for imaging-based mucus plugging. We believe that this project will increase the clinical and genetic understanding of mucus dysfunction, a clear gap in COPD, and will provide a validated imaging assessment that can be used for clinical and epidemiologic investigation.