Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and the only leading cause of death that is steadily increasing in frequency. This proposal will establish a racially diverse cohort that is sufficiently large and appropriately designed for genome-wide association analysis of COPD. A total of 10,500 subjects will be recruited, including control smokers and subjects across the full range of COPD severity (GOLD Stages 1 through 4). This cohort will be used for cross-sectional analysis, although long-term longitudinal follow-up will be a future goal. The primary focus of the study will be genome-wide association analysis to identify the genetic risk factors that determine susceptibility for COPD and COPD related phenotypes. Detailed phenotyping of COPD cases, including chest CT scan assessment of emphysema and airway disease, will allow identification of genetic determinants for the heterogeneous components of the COPD syndrome. The hypotheses to be studied are: 1) Precise phenotypic characterization of COPD subjects using computed tomography, as well as clinical and physiological measures, will provide data that will enable the broad COPD syndrome to be decomposed into clinically significant subtypes. 2) Genome-wide association studies will identify genetic determinants for COPD susceptibility that will provide insight into clinically relevant COPD subtypes. 3) Distinct genetic determinants influence the development of emphysema and airway disease. The genome-wide association analysis will involve four phases to identify COPD susceptibility genes using a case-control design.
The Specific Aims are (1) Cohort Building. Identify and phenotype COPD case and control cohorts in two racial groups (non-Hispanic whites and African Americans) for genetic and natural history studies. (2) Genome-wide Association Study. In Phase 1, a genome-wide panel of single nucleotide polymorphisms (SNPs) will be tested for association with COPD and COPD-related phenotypes in COPD case-control samples within each racial group. In Phase 2, the top-ranked 6,000 SNPs in each racial group will be validated and tested in a second round of association analysis in independent samples. In Phase 3, the genomic regions around the top-ranked 50 SNPs in each racial group will be analyzed to identify genes/regions yielding confirmed association signals. In Phase 4, final susceptibility gene identification will be performed in the entire study population, with external validation in the Boston Early-Onset COPD Study and International COPD Genetics Network. (3) Epidemiologic characterization of subtypes of COPD using the radiologic, physiologic, and clinical data including CT emphysema and airway phenotypes, degree of functional impairment, and severity of COPD, will be performed. Finally, SNPs in the identified COPD genes from Aim 2 will be tested for association with these COPD subtypes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL089897-03
Application #
7663132
Study Section
Special Emphasis Panel (ZHL1-CSR-R (S1))
Program Officer
Croxton, Thomas
Project Start
2007-09-27
Project End
2012-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
3
Fiscal Year
2009
Total Cost
$6,586,795
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206
Sakornsakolpat, Phuwanat; Morrow, Jarrett D; Castaldi, Peter J et al. (2018) Integrative genomics identifies new genes associated with severe COPD and emphysema. Respir Res 19:46
Fawzy, Ashraf; Putcha, Nirupama; Paulin, Laura M et al. (2018) Association of thrombocytosis with COPD morbidity: the SPIROMICS and COPDGene cohorts. Respir Res 19:20
Cruickshank-Quinn, Charmion I; Jacobson, Sean; Hughes, Grant et al. (2018) Metabolomics and transcriptomics pathway approach reveals outcome-specific perturbations in COPD. Sci Rep 8:17132
Rho, Ji Young; Lynch, David A; Suh, Young Ju et al. (2018) CT measurements of central pulmonary vasculature as predictors of severe exacerbation in COPD. Medicine (Baltimore) 97:e9542
Morrow, Jarrett D; Glass, Kimberly; Cho, Michael H et al. (2018) Human Lung DNA Methylation Quantitative Trait Loci Colocalize with Chronic Obstructive Pulmonary Disease Genome-Wide Association Loci. Am J Respir Crit Care Med 197:1275-1284
Glasheen, Cristie; Johnson, Eric O; Saccone, Nancy L et al. (2018) Is the Fagerström test for nicotine dependence invariant across secular trends in smoking? A question for cross-birth cohort analysis of nicotine dependence. Drug Alcohol Depend 185:127-132
Hayden, Lystra P; Hardin, Megan E; Qiu, Weiliang et al. (2018) Asthma Is a Risk Factor for Respiratory Exacerbations Without Increased Rate of Lung Function Decline: Five-Year Follow-up in Adult Smokers From the COPDGene Study. Chest 153:368-377
Han, MeiLan K; Tayob, Nabihah; Murray, Susan et al. (2018) Association between Emphysema and Chronic Obstructive Pulmonary Disease Outcomes in the COPDGene and SPIROMICS Cohorts: A Post Hoc Analysis of Two Clinical Trials. Am J Respir Crit Care Med 198:265-267
Ross, James C; Castaldi, Peter J; Cho, Michael H et al. (2018) Longitudinal Modeling of Lung Function Trajectories in Smokers with and without Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 198:1033-1042
Hancock, D B; Guo, Y; Reginsson, G W et al. (2018) Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence. Mol Psychiatry 23:1-9

Showing the most recent 10 out of 205 publications