Genetic association analysis of functional impairment in chronic obstructive pulmonary disease

Craig P. Hersh, Dawn L. DeMeo, Ross Lazarus, Juan C. Celedón, Benjamin A. Raby, Joshua O. Benditt, Gerard Criner, Barry Make, Fernando J. Martinez, Paul D. Scanlon, Frank C. Sciurba, James P. Utz, John J. Reilly, Edwin K. Silverman

Research output: Contribution to journalArticlepeer-review

94 Scopus citations


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 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-β1 (TGFB1) - that were associated with COPD-related phenotypes. In all subjects, single-nucleotide polymorphisms (SNPs) in EPHX1 (p ≤ 0.03) and in LTBP4 (p ≤ 0.03) were associated with maximal output on cardiopulmonary exercise testing. Markers in LTBP4 (p ≤ 0.05) and SFTPB (p = 0.005) were associated with 6-min walk test distance. SNPs in EPHX1 were associated with carbon monoxide diffusing capacity (p ≤ 0.04). Three SNPs in TGFB1 were associated with dyspnea (p ≤ 0.002), one of which replicated in the family study (p = 0.02). Conclusions: Polymorphisms in several genes seem to be associated with COPD-related traits other than FEV1. These associations may identify genes in pathways important for COPD pathogenesis.

Original languageEnglish (US)
Pages (from-to)977-984
Number of pages8
JournalAmerican journal of respiratory and critical care medicine
Issue number9
StatePublished - May 1 2006


  • Dyspnea
  • Emphysema
  • Exercise tolerance
  • Genetic association
  • Pulmonary function tests

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine


Dive into the research topics of 'Genetic association analysis of functional impairment in chronic obstructive pulmonary disease'. Together they form a unique fingerprint.

Cite this