COPD is the fourth-leading cause of death in the United States, and cigarette smoking has been proven to be the most important environmental contributor. DNA methylation varies with aging and with environmental exposures such as cigarette smoking, and is a critical mediator of gene expression. Additionally, there are data to suggest that DNA methylation patterns are influenced by DNA polymorphisms. Although widely studied in cancers, including lung cancer, the wide-scale investigation of variable methylation in COPD and the correlation with polymorphisms and gene expression have not been comprehensively performed. COPD has both local pulmonary and systemic manifestations, all of which are likely impacted by a combination of genetic, genomic and epigenetic pathways. We hypothesize that characterization of genome-wide DNA methylation marks will provide important scientific insights into COPD. We also hypothesize that characterizing genome-wide DNA methylation marks correlated with IREB2, HHIP and FAM13A variants may provide important insights into regulation of these three COPD candidate genes. To address these two hypotheses, the broad goals of this project include: 1) to identify methylation signatures that discriminate COPD susceptibility and COPD severity and 2) to use comparative epigenetic to identify methylation marks that are altered by cigarette smoke exposure and likely impact the development of COPD and its component processes, emphysema and airway disease. In this project, genome-wide methylation patterns will be characterized for lung tissue and blood DNA from human subjects in our Lung Tissue Population. Methylation patterns will also be characterized for murine lung DNA after in vivo exposure of wild-type C57BL/6 {susceptible) and NZW/LacJ (resistant) mice to cigarette smoke. We will use statistical modeling and comparative epigenetics to select COPD gene candidates to replicate using pyrosequencing methods in the Bronchoscopy Population, a second human cohort. This project will characterize DNA methylation marks important to COPD and will assess the epigenetic impact of variation in IREB2, HHIP and FAM13A as key COPD candidate genes. We will use comparative, translational and integrative genetics, genomics and epigenomics to identify functional features of COPD susceptibility genes. We expect methylation marks with replicated associations will provide novel insights into the pathobiology of COPD and the genetic context that influences the epigenomic impact of cigarette smoking. Lastly, we will integrate SNP variation, methylation marks and gene expression data to define the most comprehensive causal model of COPD.

Public Health Relevance

Investigation of variable patterns of gene methylation may provide important insights into risks for smoking related diseases. Epigenetic marks such as DNA methylation have been targets for novel diagnostics and therapeutic innovations in human disease. Identifying unique methylation signatures for COPD may result in a clinically relevant biomarker to enable earlier diagnosis and novel therapies for the treatment of COPD/ennphysema.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Brigham and Women's Hospital
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Budoff, Matthew J; Lutz, Sharon M; Kinney, Gregory L et al. (2018) Coronary Artery Calcium on Noncontrast Thoracic Computerized Tomography Scans and All-Cause Mortality. Circulation 138:2437-2438
Polverino, Francesca; Rojas-Quintero, Joselyn; Wang, Xiaoyun et al. (2018) A Disintegrin and Metalloproteinase Domain-8: A Novel Protective Proteinase in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 198:1254-1267
Sharma, Amitabh; Halu, Arda; Decano, Julius L et al. (2018) Controllability in an islet specific regulatory network identifies the transcriptional factor NFATC4, which regulates Type 2 Diabetes associated genes. NPJ Syst Biol Appl 4:25
Hayden, Lystra P; Cho, Michael H; Raby, Benjamin A et al. (2018) Childhood asthma is associated with COPD and known asthma variants in COPDGene: a genome-wide association study. Respir Res 19:209
Yun, Jeong H; Lamb, Andrew; Chase, Robert et al. (2018) Blood eosinophil count thresholds and exacerbations in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol 141:2037-2047.e10
Peng, Cheng; Cardenas, Andres; Rifas-Shiman, Sheryl L et al. (2018) Epigenome-wide association study of total serum immunoglobulin E in children: a life course approach. Clin Epigenetics 10:55
Morrow, Jarrett D; Cho, Michael H; Platig, John et al. (2018) Ensemble genomic analysis in human lung tissue identifies novel genes for chronic obstructive pulmonary disease. Hum Genomics 12:1
Wang, Xiaoyun; Polverino, Francesca; Rojas-Quintero, Joselyn et al. (2018) A Disintegrin and A Metalloproteinase-9 (ADAM9): A Novel Proteinase Culprit with Multifarious Contributions to COPD. Am J Respir Crit Care Med :
Lopes-Ramos, Camila M; Kuijjer, Marieke L; Ogino, Shuji et al. (2018) Gene Regulatory Network Analysis Identifies Sex-Linked Differences in Colon Cancer Drug Metabolism. Cancer Res 78:5538-5547
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

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