NHLBI TOPMed: Lung Tissue Research Consortium (LTRC)

Chronic obstructive pulmonary disease (COPD), a disease state characterized by airflow limitation that is not fully reversible, is the third leading cause of death in the U.S. COPD is a heterogeneous syndrome, with affected individuals demonstrating marked differences in lung structure (emphysema vs. airway disease); physiology (airflow obstruction); and other clinical features (e.g., exacerbations, co-morbid illnesses). Multiple genomic regions influencing COPD susceptibility have been identified by genome-wide association studies (GWAS), and rare coding variants can also influence risk for COPD. However, only a small percentage of the estimated heritability for COPD risk can be explained by known genetic loci. Like most complex diseases, COPD is influenced by multiple genetic determinants (each with modest individual effects). Emerging evidence supports the paradigm that complex disease genetic determinants are part of a network of interacting genes and proteins; perturbations of this network can increase disease risk. To identify this network, multiple Omics data will need to be analyzed with methods to account for nonlinear relationships and interactions between key genes and proteins. Our overall hypothesis is that integrated network analysis of genetic, transcriptomic, proteomic, and epigenetic data from biospecimens ranging from lung tissue to nasal epithelial cells to blood in highly phenotyped subjects will provide insights into COPD pathogenesis and heterogeneity. We will leverage the well-phenotyped, NHLBI-funded Lung Tissue Research Consortium (LTRC) to address these questions. We will perform multi-omics analysis in 1548 lung tissue and blood samples from the LTRC. With these multi-omics data, we will utilize a systems biology approach to understand relationships between multiple genetic determinants and multiple types of Omics data. We will begin by performing single Omics analyses in COPD vs. control lung, nasal, and blood samples. Next, we will integrate single Omics data with genetic variants identified by WGS to assist in fine mapping genetic determinants of COPD. We will then perform integrated network analysis of COPD with genetic and multiple Omics data using correlation-based, gene regulatory, and Bayesian networks. Subjects were recruited from Mayo Clinic, Universities of Colorado, Michigan, and Pittsburgh, and Temple University.]]>
LTRC Variables and Data ExplanationsTOPMed Whole Genome Sequencing Methods: Freeze 9TOPMed Whole Genome Sequencing Methods: Freeze 10The LTRC was formed to collect lung tissues and medical data from patients with lung diseases. The primary patient groups being studied are: those who have Chronic Obstructive Pulmonary Disease (COPD) or Interstitial Lung Disease (ILD). The majority of ILD patients have Idiopathic Pulmonary Fibrosis (IPF/UIP). Tissues and medical data from patients with other similar lung diseases as well as control tissues and data from patients who are going in to surgical units for exploratory biopsies have also been collected. Any subject willing to provide written informed consent to participate in the LTRC and to complete the LTRC evaluation process was eligible to participate. Blood samples were collected for research purposes. Lung tissue that was surgically removed for clinical indications was collected for research purposes; no additional lung tissue was obtained beyond what was required for clinical indications. LTRC subjects completed a standard questionnaire, pre- and post-bronchodilator pulmonary function testing, 6 minute walk and cardiopulmonary exercise testing, and chest CT scanning. We will focus on 1548 LTRC subjects with available lung tissue, peripheral blood DNA, and plasma: 647 COPD cases, 435 controls with normal spirometry, 248 IPF cases, and 218 PRISm.]]>
The Lung Tissue Research Consortium is an NHLBI-funded resource, started in 2004, in which excess surgical lung tissue and blood samples were collected on carefully phenotyped patients who have undergone thoracic surgery including explant for lung transplantation, lung volume reduction surgery for emphysema, lobectomy or segmentectomy for nodule resection, and biopsy for interstitial lung disease diagnosis.]]>