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.
We propose a five year longitudinal follow-up of subjects in COPDGene, an extensively phenotyped cohort of more than 10,000 non-Hispanic White and African American smokers at risk for or with COPD. Exome Chip genotyping and whole genome followed by candidate DNA sequencing will be performed to identify rare and common genetic determinants of COPD. The comprehensive clinical, imaging, and genetic data will be used to develop a new classification system for COPD.
|Bodduluri, Sandeep; Reinhardt, Joseph M; Hoffman, Eric A et al. (2017) Signs of Gas Trapping in Normal Lung Density Regions in Smokers. Am J Respir Crit Care Med 196:1404-1410|
|Busch, Robert; Hobbs, Brian D; Zhou, Jin et al. (2017) Genetic Association and Risk Scores in a Chronic Obstructive Pulmonary Disease Meta-analysis of 16,707 Subjects. Am J Respir Cell Mol Biol 57:35-46|
|Martinez, Carlos H; Freeman, Christine M; Nelson, Joshua D et al. (2017) GDF-15 plasma levels in chronic obstructive pulmonary disease are associated with subclinical coronary artery disease. Respir Res 18:42|
|Adami, Alessandra; Cao, Robert; Porszasz, Janos et al. (2017) Reproducibility of NIRS assessment of muscle oxidative capacity in smokers with and without COPD. Respir Physiol Neurobiol 235:18-26|
|Washko, George R; Kinney, Gregory L; Ross, James C et al. (2017) Lung Mass in Smokers. Acad Radiol 24:386-392|
|Farahi, Neda; Paige, Ellie; Balla, Jozef et al. (2017) Neutrophil-mediated IL-6 receptor trans-signaling and the risk of chronic obstructive pulmonary disease and asthma. Hum Mol Genet 26:1584-1596|
|Loehlein Fier, Heide; Prokopenko, Dmitry; Hecker, Julian et al. (2017) On the association analysis of genome-sequencing data: A spatial clustering approach for partitioning the entire genome into nonoverlapping windows. Genet Epidemiol 41:332-340|
|Morrow, Jarrett D; Zhou, Xiaobo; Lao, Taotao et al. (2017) Functional interactors of three genome-wide association study genes are differentially expressed in severe chronic obstructive pulmonary disease lung tissue. Sci Rep 7:44232|
|Hodgson, Shane; Griffin, Timothy J; Reilly, Cavan et al. (2017) Plasma sphingolipids in HIV-associated chronic obstructive pulmonary disease. BMJ Open Respir Res 4:e000180|
|Bhatt, Surya P; Vegas-Sánchez-Ferrero, Gonzalo; Rahaghi, Farbod N et al. (2017) Cardiac Morphometry on Computed Tomography and Exacerbation Reduction with ?-Blocker Therapy in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 196:1484-1488|
Showing the most recent 10 out of 168 publications