The overall goal of this PPG is to understand the genetic, genomic, and epigenetic determinants of variable susceptibility to develop COPD. Three COPD susceptibility loci have recently been definitively identified by genome-wide association studies???two loci on chromosome 4 (near HHIP and in FAM13A) and one locus on chromosome 15 (a block of genes including IREB2). However, the key genetic determinants in these regions and their functional impact on COPD have not been defined. The three projects In this PPG focus on Genetics (Project 1, PI: Silverman);Gene Expression (Project 2, PI: Choi);and DNA Methylation (Project 3, PI: DeMeo). These projects will build on a substantial existing infrastructure of well-phenotyped study populations, experience in phenotypic characterization of COPD, and an extensive track record of both in vitro and in vivo functional assessment of COPD pathogenesis. There are likely multiple additional COPD susceptibility loci, which need to be discovered. Some of these genetic loci may be influenced primarily by epigenetic alterations (e.g. DNA methylation) instead of, or In addition to, heritable SNP variation. Moreover, the other gene members of the pathways related to these genetic determinants of COPD are unknown, and assessment of gene expression and DNA methylation can likely provide insight into these pathways. Thus, we have included Discovery of additional gene expression and epigenetic influences on COPD susceptibility as a central focus of this PPG. In addition, the actual genetic determinants within the GWAS loci have not been proven. Thus, we have included efforts to localize the key genes within those regions. Multiple approaches will be used to accomplish this goal. Including assessment of genetic association in a population of different genetic ancestry (African Americans from the COPDGene project), analysis of gene expression among genes within GWAS loci, assessment for epigenetic changes of genes within GWAS loci, and assays of long-range gene regulation (e.g. chromosome conformation capture). In addition to Localization of the key determinants, Functional Validation will be required to confirm that specific genes are Involved in COPD pathogenesis and to understand their impact. We will employ both in vitro assessment within lung epithelial and monocyte cell lines (with validation in primary cell types) as well as in vivo assessment in murine models of underexpression (knockout) of the key genes and susceptible vs. resistant Inbred strains which are tested with long-term cigarette smoke exposure. We anticipate that these studies will provide insight into the pathways and mechanisms for COPD susceptibility.

Public Health Relevance

COPD is a major public health problem. Although It Is exciting to finally have genetic loci that almost certainly contribute to COPD susceptibility, the identification of these loci is just the beginning of a long path that could lead to improved understanding of COPD pathogenesis and, ultimately, to improved COPD treatment. This proposal will develop new insights into COPD genetics, genomics, and epigenetics, which will provide major progress toward this reality.

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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Postow, Lisa
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Brigham and Women's Hospital
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Polverino, Francesca; Laucho-Contreras, Maria E; Petersen, Hans et al. (2017) A Pilot Study Linking Endothelial Injury in Lungs and Kidneys in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 195:1464-1476
Qiu, Weiliang; Guo, Feng; Glass, Kimberly et al. (2017) Differential connectivity of gene regulatory networks distinguishes corticosteroid response in asthma. J Allergy Clin Immunol :
Busch, Robert; Hobbs, Brian D; Zhou, Jin et al. (2017) Genetic Association and Risk Scores in a Chronic Obstructive Pulmonary Disease Meta-analysis of 16,707 Subjects. Am J Respir Cell Mol Biol 57:35-46
Morrow, Jarrett D; Zhou, Xiaobo; Lao, Taotao et al. (2017) Functional interactors of three genome-wide association study genes are differentially expressed in severe chronic obstructive pulmonary disease lung tissue. Sci Rep 7:44232
Yun, Jeong H; Morrow, Jarrett; Owen, Caroline A et al. (2017) Transcriptomic Analysis of Lung Tissue from Cigarette Smoke-Induced Emphysema Murine Models and Human Chronic Obstructive Pulmonary Disease Show Shared and Distinct Pathways. Am J Respir Cell Mol Biol 57:47-58
Sonawane, Abhijeet Rajendra; Platig, John; Fagny, Maud et al. (2017) Understanding Tissue-Specific Gene Regulation. Cell Rep 21:1077-1088
Hayden, Lystra P; Hardin, Megan E; Qiu, Weiliang et al. (2017) 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 :
Lopes-Ramos, Camila M; Paulson, Joseph N; Chen, Cho-Yi et al. (2017) Regulatory network changes between cell lines and their tissues of origin. BMC Genomics 18:723
Paulson, Joseph N; Chen, Cho-Yi; Lopes-Ramos, Camila M et al. (2017) Tissue-aware RNA-Seq processing and normalization for heterogeneous and sparse data. BMC Bioinformatics 18:437
Hobbs, Brian D; de Jong, Kim; Lamontagne, Maxime et al. (2017) Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis. Nat Genet 49:426-432

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