Chronic obstructive pulmonary disease (COPD) is a complex disease of substantial public health concern, and is the 4th leading cause of mortality globally, with morbidity and mortality expected to worsen by the year 2020. Tobacco use is a major environmental risk factor in the development of COPD; however, only 10-20% of smokers develop symptomatic disease. Animal and human studies provide support for the role of genetic factors for both smoking behavior and its associated outcomes, including lung function and other manifestations of COPD, yet only a small proportion of potentially causal genes have been identified. The Lung Health Study (LHS), a 14.5-year, multicenter, randomized clinical trial aimed to determine whether a program of smoking intervention and use of an inhaled bronchodilator can slow the rate of decline in pulmonary function or alter COPD mortality, represents one of the largest COPD cohorts worldwide (N=5,887). As part of a previous NHLBI-funded study, we developed a DNA repository including >4,800 LHS participants. We plan to perform a genome-wide association study (GWAS) for COPD and associated quantitative traits in this well-characterized cohort and use existing GWAS datasets to validate our findings. Because we also hypothesize that some genes may contribute to nicotine addiction and thus tobacco use (the strongest environmental risk factor in COPD), we will test for association between genetic markers and this outcome, and will similarly validate those findings, and test for gene-environment interaction. A major strength of our application is the collaborative effort with colleagues at the James Hogg iCAPTURE Center for Cardiovascular and Pulmonary Research in Vancouver, and the LHS Data Coordinating Center at the University of Minnesota. Additional collaborations with investigators conducting GWAS in relevant datasets include those from Harvard University (the Framingham Health Study, the National Emphysema Treatment Trial/Normative Aging Study), University of Washington (the Cardiovascular Health Study), University of North Carolina (Tobacco and Genetics Network), and University of Toronto (Smoking Treatment for Ontario Patients Study). Goals of this study are: (1) to perform GWAS in European American and African American LHS subjects using a genome-wide array of 550,000 SNPs, with individual rate of decline of lung function and COPD susceptibility as the primary outcome phenotypes; (2) to cross-validate significant associations using existing GWAS data in independent populations; (3) to test for gene-environment interactions using markers associated with COPD outcomes, with a particular focus on tobacco use; and (4) to perform tests for association between the markers and outcomes reflecting nicotine addiction (e.g. sustained quitters vs. continuous smokers), and to validate significant associations in a replicate population. Findings from this study will provide a better understanding of the complex pathways related to risk of COPD and its associated phenotypes. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01HG004738-01
Application #
7514745
Study Section
Special Emphasis Panel (ZHG1-HGR-P (M1))
Program Officer
Wise, Anastasia Leigh
Project Start
2008-09-20
Project End
2010-06-30
Budget Start
2008-09-20
Budget End
2009-06-30
Support Year
1
Fiscal Year
2008
Total Cost
$590,469
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Castaldi, Peter J; Benet, Marta; Petersen, Hans et al. (2017) Do COPD subtypes really exist? COPD heterogeneity and clustering in 10 independent cohorts. Thorax 72:998-1006
John, Catherine; Soler Artigas, María; Hui, Jennie et al. (2017) Genetic variants affecting cross-sectional lung function in adults show little or no effect on longitudinal lung function decline. Thorax 72:400-408
Machiela, Mitchell J; Zhou, Weiyin; Karlins, Eric et al. (2016) Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome. Nat Commun 7:11843
Yu, Bing; Pulit, Sara L; Hwang, Shih-Jen et al. (2016) Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk. Circ Cardiovasc Genet 9:64-70
Hansel, Nadia N; Paré, Peter D; Rafaels, Nicholas et al. (2015) Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease. Am J Respir Cell Mol Biol 53:226-34
Auer, Paul L; Nalls, Mike; Meschia, James F et al. (2015) Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project. JAMA Neurol 72:781-8
Stanley, Susan E; Chen, Julian J L; Podlevsky, Joshua D et al. (2015) Telomerase mutations in smokers with severe emphysema. J Clin Invest 125:563-70
Himes, Blanca E; Qiu, Weiliang; Klanderman, Barbara et al. (2013) ITGB5 and AGFG1 variants are associated with severity of airway responsiveness. BMC Med Genet 14:86
Norton, Nadine; Li, Duanxiang; Rampersaud, Evadnie et al. (2013) Exome sequencing and genome-wide linkage analysis in 17 families illustrate the complex contribution of TTN truncating variants to dilated cardiomyopathy. Circ Cardiovasc Genet 6:144-53
Stephens, Sarah H; Hartz, Sarah M; Hoft, Nicole R et al. (2013) Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smoking. Genet Epidemiol 37:846-59

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