The identification of novel susceptibility genes for complex diseases like COPD could transform our understanding of disease pathophysiology and provide new pathways for treatment. We have recently collaborated in case-control genome-wide association studies that have provided compelling evidence for association of COPD susceptibility with regions on chromosome 15 (near IREB2), chromosome 4 (near HHIP), and another region on chromosome 4 (in FAM13A). However, the key genes within these GWAS loci have not been absolutely verified, and the key functional variants within these GWAS loci have not been identified. We will address several key hypotheses that will assist in the localization of functional genetic determinants within GWAS loci and investigation of their biological mechanisms: 1) African Americans and non-Hispanic Whites will share a subset of COPD genetic determinants;assessing the overlap of genetic association between these groups will localize COPD susceptibility genes;2) Many of the functional variants influencing COPD susceptibility will regulate gene expression;and 3) Studies of Fami3a, Hhip, and /reib2 knockout mice exposed to cigarette smoke will identify the activities of these genes in COPD pathogenesis. In order to address these hypotheses and to identify potentially functional variants influencing COPD susceptibility, we will begin by localizing functional variants for COPD susceptibility in three existing GWAS loci (HHIP, FAM13A, and IREB2) using association analysis of dense SNP panels in African-American subjects from COPDGene to narrow shared COPD susceptibility regions between African-American and non-Hispanic White subjects. To localize key variants, we will assess regulatory regions around genes in these GWAS loci using chromosome conformation capture and chromatin immunoprecipitation assays. We will also assess the impact of specific variants in the regulatory region in luciferase reporter assays. We will use shRNA-mediated silencing of genes in the GWAS loci to assess whether these genes regulate the function of lung epithelial and monocyte cells lines and validate these results in primary cells. Finally, the impact of three key regional genes in GWAS loci on COPD pathogenesis will be assessed in knockout mice exposed to cigarette smoke. This project will identify the key COPD genes within GWAS loci and demonstrate the functional impact of those genes on COPD susceptibility. The multidisciplinary investigations of genetic association, genomic interactions, in vitro cell-based assays, and cigarette smokeexpose knockout mice in this project will provide important and novel insights into COPD pathogenesis.

Public Health Relevance

Recent genetic studies have found areas of the human genome that influence the risk of developing chronic obstructive pulmonary disease (COPD) in cigarette smokers. This project will find the specific genes in these areas and begin to determine why these genes are responsible for COPD risk. This study will improve our understanding of COPD, and it is an important first step towards developing new treatments for COPD.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
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

Showing the most recent 10 out of 101 publications