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Logo of patsIssue Featuring ArticlePublisher's Version of ArticleSubmissionsAmerican Thoracic SocietyAmerican Thoracic SocietyProceedings of the American Thoracic Society
 
Proc Am Thorac Soc. Aug 2006; 3(6): 476.
PMCID: PMC2647635
Genetic Determinants of Functional Impairment in Chronic Obstructive Pulmonary Disease
Craig P. Hersh, Dawn L. DeMeo, Ross Lazarus, Juan C. Celedón, Benjamin A. Raby, John J. Reilly, and Edwin K. Silverman
Channing Laboratory and Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
Correspondence and requests for reprints should be addressed to Craig P. Hersh, M.D., M.P.H., Channing Laboratory, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115. E-mail: craig.hersh/at/channing.harvard.edu
Received March 16, 2006; Accepted April 11, 2006.
 
Rationale: Patients with severe chronic obstructive pulmonary disease (COPD) may have varying levels of disability despite similar levels of lung function. This variation may reflect different COPD subtypes, which may have different genetic predispositions. Methods: In 304 subjects from the National Emphysema Treatment Trial, we genotyped 80 markers in 22 positional and/or biologically plausible candidate genes. Regression models were used to test for association, using a test-replication approach to guard against false-positive results. For significant associations, effect estimates were recalculated using the entire cohort. Positive associations with dyspnea were confirmed in families from the Boston Early-Onset COPD Study. Results: The test-replication approach identified four genes—microsomal epoxide hydrolase (EPHX1), latent transforming growth factor β binding protein-4 (LTBP4), surfactant protein B (SFTPB), and transforming growth factor β-1 (TGFB1)—that were associated with COPD-related phenotypes. In all subjects, single nucleotide polymorphisms (SNPs) in EPHX1 (p [less-than-or-eq, slant] 0.03) and in LTBP4 (p [less-than-or-eq, slant] 0.03) were associated with maximal output on cardiopulmonary exercise testing. Markers in LTBP4 (p [less-than-or-eq, slant] 0.05) and SFTPB (p = 0.005) were associated with six-minute walk test distance. SNPs in EPHX1 were associated with carbon monoxide diffusing capacity (p [less-than-or-eq, slant] 0.04). Three SNPs in TGFB1 were associated with dyspnea (p [less-than-or-eq, slant] 0.002), one of which replicated in the family study (p = 0.02). Conclusions: Polymorphisms in several genes appear to be associated with COPD-related traits other than forced expiratory volume in 1 second. These associations may identify genes in pathways important for COPD pathogenesis.
Notes
Supported by NIH grants HL71393 (Edwin Silverman), HL075478 (Edwin Silverman), N01HR76102 (John Reilly), HL080242 (Craig Hersh), and by an American Lung Association Career Investigator Award (Edwin Silverman).
Conflict of Interest Statement: C.P.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.L.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.C.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. B.A.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.J.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. E.K.S. received grant support, consulting fees, and honoraria from GlaxoSmithKline for studies of COPD genetics. He also received a speaker fee from Wyeth for a talk on COPD genetics and also received honoraria from Bayer.
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