Chronic obstructive pulmonary disease (COPD) and asthma are traditionally considered as two separate diseases. However, between 15-45% of COPD patients additionally report a history of asthma. Subjects with both COPD and asthma are an important clinical subgroup, with increased symptoms, exacerbations and hospitalizations. COPD can be readily diagnosed using spirometry, yet there is no gold standard test for asthma. Therefore, recent guidelines have provided a list of largely clinical features to identify patients with the asthma-COPD overlap syndrome (ACOS). We hypothesize that improvements in phenotype definition will be required to make progress in population studies of the epidemiology and genomics of ACOS. However, few large cohorts are amenable to this investigation. In the Genetic Epidemiology of COPD Study (COPDGene), our group has identified clinical, imaging, and genetic features of ACOS, defined by questionnaire. In this proposal, we will address the phenotyping and genomics of ACOS through the following Specific Aims. (1) Peripheral blood biomarkers of the ACOS phenotype: We will test the hypothesis that asthma biomarkers can improve the definition of ACOS. We will measure total and specific Immunoglobulin E (IgE) levels in COPDGene. Blood eosinophil counts are being measured in phase 2 of COPDGene. We will examine baseline and longitudinal clinical and chest CT imaging features of ACOS subjects with allergic sensitization and/or peripheral eosinophilia compared to usual COPD. (2) Gene expression in ACOS: We will test the hypothesis that ACOS has distinct biologic influences compared to usual COPD. We will perform RNA sequencing on peripheral blood samples to identify differentially expressed transcripts in ACOS subjects with allergic sensitization or peripheral eosinophilia compared to usual COPD. We will integrate the RNA-seq results with genomewide single nucleotide polymorphism (SNP) data to identify eQTL SNPs associated with transcript levels of the differentially expressed genes. (3) Systems genomics in ACOS: We will test potential functional mechanisms and genetic regulatory effects important in ACOS, identified using network methods. In sub-aim (a), we will construct gene networks using the RNA-seq data, compare regulatory connections in ACOS and usual COPD, and identify the genes most central to the differences between these networks. In sub-aim (b), we will perform in vitro validation of the networks using siRNA knockdown of key genes in lymphoblastoid cell lines from subjects with ACOS and usual COPD. Using asthma biomarkers and RNA-seq data to discover genetic influences on the clinically-relevant asthma-COPD overlap syndrome could identify objective diagnostic markers of ACOS or novel pathways and targets, moving towards the goal of precision medicine in COPD. The large-scale biomarker and RNA-seq datasets will serve as resources for COPDGene and the community of COPD investigators.

Public Health Relevance

Patients with both asthma and COPD have more healthcare needs than patients with either disease alone. In the 'Systems Genomics of the Asthma-COPD Overlap Syndrome' study, we will test a better way to diagnose this group of patients, and we will search for the genes responsible. The information we learn may eventually lead to a more personalized approach to the diagnosis and treatment of patients with COPD and asthma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL130512-02
Application #
9226025
Study Section
Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Gan, Weiniu
Project Start
2016-03-01
Project End
2020-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
2
Fiscal Year
2017
Total Cost
$887,102
Indirect Cost
$387,326
Name
Brigham and Women's Hospital
Department
Type
Independent Hospitals
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Seo, Minseok; Qiu, Weiliang; Bailey, William et al. (2018) Genomics and response to long-term oxygen therapy in chronic obstructive pulmonary disease. J Mol Med (Berl) 96:1375-1385
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
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
Zarei, Sara; Mirtar, Ali; Morrow, Jarrett D et al. (2017) Subtyping Chronic Obstructive Pulmonary Disease Using Peripheral Blood Proteomics. Chronic Obstr Pulm Dis 4:97-108
Parker, Margaret M; Chase, Robert P; Lamb, Andrew et al. (2017) RNA sequencing identifies novel non-coding RNA and exon-specific effects associated with cigarette smoking. BMC Med Genomics 10:58
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
Hersh, Craig P (2017) Diagnosing alpha-1 antitrypsin deficiency: the first step in precision medicine. F1000Res 6:2049
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

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