(1 of 2) Genetic Epidemiology of COPD

描述(由申请人提供)：项目摘要/摘要慢性阻塞性肺疾病(COPD)是美国第三大致死原因，是一种异质综合征。全面了解COPD的异质性将需要纵向数据来阐明疾病进展的遗传、临床和放射学决定因素。这项建议将通过对所有可用的COPDgene受试者进行为期5年的纵向随访来延长COPDgene研究，并对除对照吸烟者外的所有受试者进行后续的胸部CT扫描，基线CT扫描正常。COPD基因的主要目标是：a)确定影响COPD和COPD相关表型发展的新的遗传基因；b)将COPD重新分类为亚型，最终可用于开发有效的针对亚型的疗法。这种更新应用的主要假设是，通过结合影像、临床和遗传特征，可以识别在病理生理机制和疾病进展方面不同的COPD亚型。具体目标是：1)使用临床表型和胸部CT扫描的定量和视觉分析来表征COPD在五年内进展的决定因素；2)通过使用Exome芯片对10,171名受试者进行基因分型，然后对2,000名具有特定成像特征的受试者进行全基因组测序，并验证其余8,171名COPD基因受试者中罕见的变异关联，来评估COPD和COPD相关表型的罕见和常见的遗传决定因素；以及3)通过整合基于遗传、临床、生理和CT的表型，开发基于COPD病理生理亚型的新的分类系统。这一新的COPD分类系统将在多个合作的COPD队列中得到验证。

DESCRIPTION (provided by applicant): PROJECT SUMMARY / ABSTRACT Chronic obstructive pulmonary disease (COPD), the third leading cause of death in the United States, is a heterogeneous syndrome. Comprehensive insight into COPD heterogeneity will require longitudinal data to elucidate the genetic, clinical, and radiographic determinants of disease progression. This proposal will extend the COPDGene Study by performing five-year longitudinal follow-up visits on all available COPDGene subjects, with follow-up chest CT scans on all subjects except control smokers with normal baseline CT scans. The primary goals of COPDGene are: a) To identify new genetic loci that influence the development of COPD and COPD-related phenotypes; and b) To reclassify COPD into subtypes that can ultimately be used to develop effective subtype-specific therapies. The primary hypothesis for this renewal application is that subtypes of COPD which differ in pathophysiological mechanism and disease progression can be identified by integrating imaging, clinical, and genetic characteristics. The specific aims are: 1) To characterize the determinants of COPD progression over five years using clinical phenotyping and both quantitative and visual analysis of chest CT scans; 2) To assess the rare and common genetic determinants of COPD and COPD- related phenotypes by genotyping with the Exome Chip in 10,171 subjects, followed by whole genome sequencing of 2,000 subjects with specific imaging characteristics and validation of the rare variant associations in the remaining 8,171 COPDGene subjects; and 3) To develop a new classification system based on pathophysiologic subtypes of COPD by integrating genetic, clinical, physiologic, and CT-based phenotypes. This novel COPD classification system will be validated in multiple collaborating COPD cohorts.