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

吸烟者粘液堵塞的临床意义、基因组学和转录

• 批准号: 10641902
• 负责人: MICHAEL H. CHO
• 金额: $ 81.88万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-09 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641902
• 关键词: Acute; Affect; Bronchial Tree; Cause of Death; Cells; Cessation of life; Chronic; Chronic Bronchitis; Chronic Obstructive Pulmonary Disease; Clinical; Clinical Research; Coughing; Cutis Laxa; Data; Data Reporting; Development; Disease; Enrollment; Epithelial Cells; Evaluation; Exudate; Flare; Functional disorder; Gene Expression; General Population; Genetic; Genetic Determinism; Genetic Predisposition to Disease; Genetic Transcription; Genetic Variation; Genetic study; Genomics; Genotype; Hyperplasia; Image; Knowledge; Lung; Measures; Meta-Analysis; Metaplasia; Military Personnel; Modeling; Mucous body substance; Nasal Epithelium; Outcome; Patient Self-Report; Persons; Phase; Phenotype; Population; Process; Production; Pulmonary Emphysema; Reporting; Reproducibility; Respiratory Disease; Respiratory Signs and Symptoms; Risk Factors; Scanning; Severity of illness; Shortness of Breath; Smoker; Smoking; Sputum; Structure of parenchyma of lung; Surrogate Endpoint; Susceptibility Gene; Syndrome; Testing; Tissue Sample; Tissue-Specific Gene Expression; Trans-Omics for Precision Medicine; United States; Visual; X-Ray Computed Tomography; airway obstruction; alpha 1-Antitrypsin Deficiency; asthmatic; bronchial epithelium; chest computed tomography; cigarette smoke-induced; cigarette smoking; clinical investigation; clinically relevant; cohort; differential expression; disease heterogeneity; disease phenotype; epidemiology study; follow-up; gene discovery; genetic makeup; genetic variant; genome sequencing; genome wide association study; genome-wide; hazard; imaging detection; insight; longitudinal analysis; lung cancer screening; mortality; mucus clearance; mucus hypersecretion; novel therapeutics; persistent symptom; pulmonary function; transcriptomics; whole genome

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.

项目概要/摘要 气流阻塞是慢性阻塞性肺疾病（COPD）的一个明确的病理生理学特征。 COPD 影响约 2890 万人，是美国第三大死因。 尽管慢性阻塞性肺病的主要危险因素是吸烟，但也有证据表明遗传易感性。 单基因综合征——Alpha-1 抗胰蛋白酶缺乏症和皮肤松弛——患有肺气肿，这是一种慢性阻塞性肺病 表型，作为其表现的一部分，导致气流的病理生理学特征。 COPD 中的阻塞是粘液功能障碍 香烟烟雾引起的粘液功能障碍导致粘液功能障碍增加。 粘液的产生和清除减少导致其在气道中积聚并形成堵塞， 进而导致气流阻塞 肺组织研究表明，小气道闭塞。 粘液渗出物与疾病的严重程度和死亡率相关，强调了粘液的临床相关性 目前 COPD 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（例如慢性咳嗽、痰和肺组织）来反映这一点 紊乱 etc。 在本提案中，我们将通过胸部计算机断层扫描 (CT) 直观地识别粘液堵塞并对其进行评分 纳入 COPDGene 的受试者，对 COPD 进行纵向评估以识别预测替代终点 - 点 (ECLIPSE) 和军事人员早期肺癌检测 (DECAMP)-2 研究 — 大型 在目标 1 中，我们将在第 1、2 和 3 阶段 CT 中对吸烟者进行视觉评分。 然后我们将确定与 10 年 CT 变化相关的因素。 确定了粘液堵塞以及该成像特征与急性呼吸道疾病的关联 在目标 2 中，我们将对所有基线 ECLIPSE CT 扫描中的粘液堵塞进行评分，并使用 来自目标 1 的 COPDGene 分数，用于执行全基因组关联研究，以确定常见和 与 CT 识别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， 然后我们将测试这些关联。 使用荟萃分析比较 CT 识别的粘液堵塞与常见和罕见的遗传变异之间的关系 最后，在目标 3 中，我们将对吸烟者的 CT 扫描中的粘液堵塞情况进行评分。 参加 DECAMP-2 研究将在收集的支气管和鼻腔中进行转录组分析。 我们认为，通过上皮细胞来识别基于成像的粘液堵塞的基因表达差异。 该项目将增加对粘液功能障碍、慢性阻塞性肺病的明显差距的临床和遗传学认识，并将 提供经过验证的影像评估，可用于临床和流行病学调查。

项目成果

Association between Cardiorespiratory Fitness and Bronchiectasis at CT: A Long-term Population-based Study of Healthy Young Adults Aged 18-30 Years in the CARDIA Study.

CT 心肺健康与支气管扩张之间的关联：CARDIA 研究中针对 18-30 岁健康年轻人的长期人群研究。

• DOI: 10.1148/radiol.2021203874
• 发表时间: 2021
• 期刊: Radiology
• 影响因子: 19.7
• 作者: Diaz,AlejandroA;Colangelo,LauraA;Okajima,Yuka;Yen,Andrew;Sala,MarcA;Dransfield,MarkT;Tino,Gregory;Ross,JamesC;SanJoséEstépar,Raúl;Washko,GeorgeR;Kalhan,Ravi
• 通讯作者: Kalhan,Ravi

Mucus plugging on computed tomography and chronic bronchitis in chronic obstructive pulmonary disease.

• DOI: 10.1186/s12931-021-01712-0
• 发表时间: 2021-04-17
• 期刊: Respiratory research
• 影响因子: 5.8
• 作者: Kim V;Dolliver WR;Nath HP;Grumley SA;Terry N;Ahmed A;Yen A;Jacobs K;Kligerman S;Diaz AA;COPDGene Investigators
• 通讯作者: COPDGene Investigators

Causes of and Clinical Features Associated with Death in Tobacco Cigarette Users by Lung Function Impairment.

吸烟者因肺功能损伤死亡的原因和相关临床特征。

• DOI: 10.1164/rccm.202210-1887oc
• 发表时间: 2023
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Labaki,WassimW;Gu,Tian;Murray,Susan;Curtis,JeffreyL;Wells,JMichael;Bhatt,SuryaP;Bon,Jessica;Diaz,AlejandroA;Hersh,CraigP;Wan,EmilyS;Kim,Victor;Beaty,TerriH;Hokanson,JohnE;Bowler,RussellP;Arenberg,DouglasA;Kazerooni
• 通讯作者: Kazerooni

Prevalence and Population Attributable Risk for Early Chronic Obstructive Pulmonary Disease in U.S. Hispanic/Latino Individuals.

美国西班牙裔/拉丁裔人群早期慢性阻塞性肺疾病的患病率和人群归因风险。

• DOI: 10.1513/annalsats.202103-253oc
• 发表时间: 2022
• 期刊: Annals of the American Thoracic Society
• 影响因子: 8.3
• 作者: Khalid,Fariha;Wang,Wei;Mannino,David;Diaz,AlejandroA
• 通讯作者: Diaz,AlejandroA

Unsupervised representation learning improves genomic discovery and risk prediction for respiratory and circulatory functions and diseases.

无监督表示学习改善了呼吸和循环功能及疾病的基因组发现和风险预测。

• DOI: 10.1101/2023.04.28.23289285
• 发表时间: 2023
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Yun,Taedong;Cosentino,Justin;Behsaz,Babak;McCaw,ZacharyR;Hill,Davin;Luben,Robert;Lai,Dongbing;Bates,John;Yang,Howard;Schwantes-An,Tae-Hwi;Zhou,Yuchen;Khawaja,AnthonyP;Carroll,Andrew;Hobbs,BrianD;Cho,MichaelH;McLean,Cory
• 通讯作者: McLean,Cory