(1 of 2) Genetic Epidemiology of COPD

慢性阻塞性肺疾病（COPD）是美国第三大死亡原因，是一种异质性综合征。全面了解COPD异质性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。该提案将通过对所有可用的COPDGene受试者进行5年的纵向随访来扩展COPDGene研究，并对除基线CT扫描正常的对照吸烟者外的所有受试者进行随访胸部CT扫描。COPDGene的主要目标是：a)发现影响COPD和COPD相关表型发展的新基因位点；b)将COPD重新分类为亚型，最终可用于开发有效的亚型特异性治疗方法。这项新应用的主要假设是，COPD的病理生理机制和疾病进展不同的亚型可以通过综合影像学、临床和遗传特征来识别。具体目的是：1)通过临床表型和胸部CT扫描的定量和视觉分析来表征COPD进展的决定因素。2)通过使用Exome Chip对10,171名受试者进行基因分型，评估COPD和COPD相关表型的罕见和常见遗传决定因素，随后对2,000名具有特定影像学特征的受试者进行全基因组测序，并验证其余8,171名COPDGene受试者的罕见变异关联；3)综合遗传、临床、生理和ct表型，建立基于慢性阻塞性肺病病理生理亚型的新分类体系。这种新的COPD分类系统将在多个合作COPD队列中进行验证。

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.