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)
Type
Research Project (R01)
Project #
3R01HL089856-08S1
Application #
8925966
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Gan, Weiniu
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Zhou, Jin J; Hu, Tao; Qiao, Dandi et al. (2016) Boosting Gene Mapping Power and Efficiency with Efficient Exact Variance Component Tests of SNP Sets. Genetics :
Mathias, Rasika Ann; Taub, Margaret A; Gignoux, Christopher R et al. (2016) A continuum of admixture in the Western Hemisphere revealed by the African Diaspora genome. Nat Commun 7:12522
Begum, Ferdouse; Ruczinski, Ingo; Li, Shengchao et al. (2016) Identifying a Deletion Affecting Total Lung Capacity Among Subjects in the COPDGene Study Cohort. Genet Epidemiol 40:81-8
Kinney, Gregory L; Baker, Emma H; Klein, Oana L et al. (2016) Pulmonary Predictors of Incident Diabetes in Smokers. Chronic Obstr Pulm Dis 3:739-747
Lu, Qiongshi; Jin, Chentian; Sun, Jiehuan et al. (2016) Post-GWAS Prioritization Through Data Integration Provides Novel Insights on Chronic Obstructive Pulmonary Disease. Stat Biosci 2016:1-17
Bhatt, Surya P; Soler, Xavier; Wang, Xin et al. (2016) Association between Functional Small Airway Disease and FEV1 Decline in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 194:178-84
Hardin, M; Cho, M H; McDonald, M-L et al. (2016) A genome-wide analysis of the response to inhaled β2-agonists in chronic obstructive pulmonary disease. Pharmacogenomics J 16:326-35
Putman, Rachel K; Hatabu, Hiroto; Araki, Tetsuro et al. (2016) Association Between Interstitial Lung Abnormalities and All-Cause Mortality. JAMA 315:672-81
Bhatt, Surya P; Wells, James M; Kinney, Gregory L et al. (2016) β-Blockers are associated with a reduction in COPD exacerbations. Thorax 71:8-14
Leidy, Nancy K; Malley, Karen G; Steenrod, Anna W et al. (2016) Insight into Best Variables for COPD Case Identification: A Random Forests Analysis. Chronic Obstr Pulm Dis (Miami) 3:406-418

Showing the most recent 10 out of 130 publications