Cigarette smoking is the major environmental risk factor for chronic obstructive pulmonary disease (COPD);however, the development of COPD is markedly variable among smokers, and genetic factors likely influence this variability. Candidate gene association studies have identified several potential COPD susceptibility genes, and genome-wide association studies promise to confirm multiple COPD susceptibility loci. However, association studies typically do not identify the functional variants in associated genes. Moreover, rare variants may contribute to COPD susceptibility, and association studies of attainable sample sizes cannot assess their impact. In the Boston Early-Onset COPD Study, positional cloning efforts have localized several potential COPD susceptibility loci, and rare variant analysis in this study has identified a potentially functional variant in elastin which may influence COPD susceptibility. In order to identify both rare and common genetic variants influencing COPD susceptibility, we will perform dense resequencing of 10 candidate genes identified from previous and ongoing genetic association studies. To characterize the genetic variation of these candidate genes comprehensively, resequencing of the complete genomic sequence of these 10 genes will be performed in three sets of case-control subjects: A) 180 severe, early-onset COPD probands and 180 of their smoking relatives with normal FEV1 values;b) 200 National Emphysema Treatment Trial (NETT) COPD cases and 200 Normative Aging Study (NAS) smoking control subjects;and 200 International COPD Genetics Network (ICGN) COPD cases and 200 ICGN smoking control subjects. Rare variant analysis will be performed by comparing the frequency of non-synonymous SNPs in COPD cases and controls. Common variants will be tested for genetic association in five populations: A) NETT cases and NAS controls;b) two sets of Boston Early-Onset COPD Study families;c) ICGN families;and d) African-American COPD cases and controls. Potentially functional rare and common variants will be tested for their effects on gene expression in lymphoblastoid cell lines of early-onset COPD probands by comparing heteronuclear RNA (pre- mRNA) levels across genotypes and by performing allelic imbalance expression analysis. If novel COPD susceptibility genes can be found, new pharmacological interventions for COPD could be developed, improved understanding of COPD pathophysiology could result, and susceptible individuals could be identified.

Public Health Relevance

Chronic obstructive pulmonary disease (COPD) is likely influenced by genetic factors, but the only proven genetic determinant of COPD is severe alpha 1-antitrypsin (AAT) deficiency. In order to identify novel common and rare genetic determinants of COPD, resequencing potential susceptibility genes in large numbers of COPD and control subjects will be performed. Genetic association studies of common variants will be undertaken in multiple populations, and functional studies of identified variants will be performed.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075478-08
Application #
8243559
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Postow, Lisa
Project Start
2003-12-19
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
8
Fiscal Year
2012
Total Cost
$846,892
Indirect Cost
$372,443
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Wang, Longfei; Lee, Sungyoung; Gim, Jungsoo et al. (2016) Family-Based Rare Variant Association Analysis: A Fast and Efficient Method of Multivariate Phenotype Association Analysis. Genet Epidemiol 40:502-11
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, Michael J; Yates, Katherine P; Zhou, Xiaobo et al. (2016) Patterns of Growth and Decline in Lung Function in Persistent Childhood Asthma. N Engl J Med 374:1842-52
Choi, Sungkyoung; Lee, Sungyoung; Qiao, Dandi et al. (2016) FARVATX: Family-Based Rare Variant Association Test for X-Linked Genes. Genet Epidemiol 40:475-85
Lao, Taotao; Jiang, Zhiqiang; Yun, Jeong et al. (2016) Hhip haploinsufficiency sensitizes mice to age-related emphysema. Proc Natl Acad Sci U S A 113:E4681-7
Jiang, Zhiqiang; Lao, Taotao; Qiu, Weiliang et al. (2016) A Chronic Obstructive Pulmonary Disease Susceptibility Gene, FAM13A, Regulates Protein Stability of β-Catenin. Am J Respir Crit Care Med 194:185-97
Lao, Taotao; Glass, Kimberly; Qiu, Weiliang et al. (2015) Haploinsufficiency of Hedgehog interacting protein causes increased emphysema induced by cigarette smoke through network rewiring. Genome Med 7:12
Lee, Jin Hwa; Cho, Michael H; Hersh, Craig P et al. (2015) IREB2 and GALC are associated with pulmonary artery enlargement in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 52:365-76
McDonald, Merry-Lynn Noelle; Mattheisen, Manuel; Cho, Michael H et al. (2014) Beyond GWAS in COPD: probing the landscape between gene-set associations, genome-wide associations and protein-protein interaction networks. Hum Hered 78:131-9
Chu, Jen-hwa; Hersh, Craig P; Castaldi, Peter J et al. (2014) Analyzing networks of phenotypes in complex diseases: methodology and applications in COPD. BMC Syst Biol 8:78

Showing the most recent 10 out of 68 publications