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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL089897-08
Application #
8700462
Study Section
Special Emphasis Panel (ZHL1-CSR-X (M2))
Program Officer
Postow, Lisa
Project Start
2007-07-01
Project End
2017-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
8
Fiscal Year
2014
Total Cost
$7,411,479
Indirect Cost
$1,005,685
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206
McDonald, Merry-Lynn N; Cho, Michael H; Sørheim, Inga-Cecilie et al. (2014) Common genetic variants associated with resting oxygenation in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 51:678-87
Bowler, Russell P; Kim, Victor; Regan, Elizabeth et al. (2014) Prediction of acute respiratory disease in current and former smokers with and without COPD. Chest 146:941-50
Hersh, Craig P; Make, Barry J; Lynch, David A et al. (2014) Non-emphysematous chronic obstructive pulmonary disease is associated with diabetes mellitus. BMC Pulm Med 14:164
Kim, Victor; Davey, Adam; Comellas, Alejandro P et al. (2014) Clinical and computed tomographic predictors of chronic bronchitis in COPD: a cross sectional analysis of the COPDGene study. Respir Res 15:52
Cho, Michael H; McDonald, Merry-Lynn N; Zhou, Xiaobo et al. (2014) Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis. Lancet Respir Med 2:214-25
Castaldi, Peter J; Dy, Jennifer; Ross, James et al. (2014) Cluster analysis in the COPDGene study identifies subtypes of smokers with distinct patterns of airway disease and emphysema. Thorax 69:415-22
Qiao, Dandi; Cho, Michael H; Fier, Heide et al. (2014) On the simultaneous association analysis of large genomic regions: a massive multi-locus association test. Bioinformatics 30:157-64
Chu, Jen-hwa; Hersh, Craig P; Castaldi, Peter J et al. (2014) Analyzing networks of phenotypes in complex diseases: methodology and applications in COPD. BMC Syst Biol 8:78
Parker, Margaret M; Foreman, Marilyn G; Abel, Haley J et al. (2014) Admixture mapping identifies a quantitative trait locus associated with FEV1/FVC in the COPDGene Study. Genet Epidemiol 38:652-9
Lee, Jin Hwa; McDonald, Merry-Lynn N; Cho, Michael H et al. (2014) DNAH5 is associated with total lung capacity in chronic obstructive pulmonary disease. Respir Res 15:97

Showing the most recent 10 out of 30 publications