Published ahead of print on February 2, 2006, doi:10.1164/rccm.200509-1452OC
Am. J. Respir. Crit. Care Med., Volume 173, Number 9, May 2006, 977-984
A more recent version of this article appeared on May 1, 2006
Submitted on September 17, 2005
Accepted on January 31, 2006
Genetic Association Analysis of Functional Impairment in Chronic Obstructive Pulmonary Disease
Craig P Hersh1*, Dawn L DeMeo1, Ross Lazarus2, Juan C Celedon2, Benjamin A Raby2, Joshua O Benditt3, Gerard Criner4, Barry Make5, Fernando J Martinez6, Paul D Scanlon7, Frank C Sciurba8, James P Utz7, John J Reilly9, and Edwin K Silverman1
1 Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA,
2 Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA,
3 University of Washington, Seattle, WA, USA,
4 Temple University, Philadelphia, PA, USA,
5 National Jewish Medical and Research Center, Denver, CO, USA,
6 University of Michigan, Ann Arbor, MI, USA,
7 Mayo Clinic, Rochester, MN, USA,
8 University of Pittsburgh, Pittsburgh, PA, USA,
9 Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: craig.hersh{at}channing.harvard.edu.
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.
Objectives: To identify genetic associations for COPD-related phenotypes, including measures of exercise capacity, pulmonary function, and respiratory symptoms.
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 re-calculated 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 beta binding protein-4 (LTBP4), surfactant protein B (SFTPB), and transforming growth factor beta-1 (TGFB1) - that were associated with COPD-related phenotypes. In all subjects, single nucleotide polymorphisms (SNPs) in EPHX1 (p 0.03) and in LTBP4 (p0.03) were associated with maximal output on cardiopulmonary exercise testing. Markers in LTBP4 (p0.05) and SFTPB (p=0.005) were associated with six-minute walk test distance. SNPs in EPHX1 were associated with carbon monoxide diffusing capacity (p0.04). Three SNPs in TGFB1 were associated with dyspnea (p0.002), 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.
Key words: dyspnea, emphysema, exercise tolerance, pulmonary function tests, genetic association
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