Substantial evidence indicates that susceptibility to chronic obstructive pulmonary disease (COPD) is influenced by genetic factors, yet identification of causative variants remains challenging. Most genetic studies of complex diseases such as COPD have focused on the role of common genetic variation. However, several complex disease studies have demonstrated the importance of rare variants;these variants have typically been of relatively strong effect. This proposal will test the hypothesis that both rare and common variants in candidate genes from monogenic human syndromes, genome-wide association studies, and/or mouse emphysema models contribute to COPD susceptibility. We will test this hypothesis in 400 subjects with severe emphysema from the National Emphysema Treatment Trial and a set of 400 smoking controls with normal lung function from the Normative Aging Study, using second-generation sequencing technology.
The specific aims are 1) variation discovery using a targeted, multiplexed approach on the Illumina Genome Analyzer;2) rare variant analysis, using a collapsing method to combine variants and increase power, and 3) common variant analysis, including replication in the Boston Early-Onset COPD Study.
PUBLIC HEALTH RELEVANCE STATEMENT COPD is the fourth leading cause of death in the US. A comprehensive understanding of the genetic risk factors and pathobiology may lead to improvements in personalized diagnosis and treatment.
|Kinney, Gregory L; Santorico, Stephanie A; Young, Kendra A et al. (2018) Identification of Chronic Obstructive Pulmonary Disease Axes That Predict All-Cause Mortality: The COPDGene Study. Am J Epidemiol 187:2109-2116|
|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|
|Schabdach, Jenna; Wells 3rd, William M; Cho, Michael et al. (2017) A Likelihood-Free Approach for Characterizing Heterogeneous Diseases in Large-Scale Studies. Inf Process Med Imaging 10265:170-183|
|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|
|Putman, Rachel K; Hatabu, Hiroto; Araki, Tetsuro et al. (2016) Association Between Interstitial Lung Abnormalities and All-Cause Mortality. JAMA 315:672-81|
|Szul, Tomasz; Castaldi, Peter; Cho, Michael H et al. (2016) Genetic regulation of expression of leukotriene A4 hydrolase. ERJ Open Res 2:|
|Chang, Yale; Glass, Kimberly; Liu, Yang-Yu et al. (2016) COPD subtypes identified by network-based clustering of blood gene expression. Genomics 107:51-58|
|Hobbs, Brian D; Parker, Margaret M; Chen, Han et al. (2016) Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 194:48-57|
|Qiao, Dandi; Lange, Christoph; Beaty, Terri H et al. (2016) Exome Sequencing Analysis in Severe, Early-Onset Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 193:1353-63|
|McGeachie, M J; Yates, K P; Zhou, X et al. (2016) Patterns of Growth and Decline in Lung Function in Persistent Childhood Asthma. N Engl J Med 374:1842-1852|
Showing the most recent 10 out of 39 publications