title: Genetic association analysis of functional impairment in chronic obstructive pulmonary disease.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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-beta binding protein-4 (LTBP4), surfactant protein B (SFTPB), and transforming growth factor-beta1 (TGFB1)-that were associated with COPD-related phenotypes. In all subjects, single-nucleotide polymorphisms (SNPs) in EPHX1 (p < or = 0.03) and in LTBP4 (p < or = 0.03) were associated with maximal output on cardiopulmonary exercise testing. Markers in LTBP4 (p < or = 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 < or = 0.04). Three SNPs in TGFB1 were associated with dyspnea (p < or = 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 FEV(1). These associations may identify genes in pathways important for COPD pathogenesis.
authors.affiliation: Channing Laboratory, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115, USA. craig.hersh@channing.harvard.edu
authors.forename: Craig P
authors.initials: CP
authors.lastname: Hersh
authors.forename: Dawn L
authors.initials: DL
authors.lastname: Demeo
authors.forename: Ross
authors.initials: R
authors.lastname: Lazarus
authors.forename: Juan C
authors.initials: JC
authors.lastname: Celedón
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Raby
authors.forename: Joshua O
authors.initials: JO
authors.lastname: Benditt
authors.forename: Gerard
authors.initials: G
authors.lastname: Criner
authors.forename: Barry
authors.initials: B
authors.lastname: Make
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Martinez
authors.forename: Paul D
authors.initials: PD
authors.lastname: Scanlon
authors.forename: Frank C
authors.initials: FC
authors.lastname: Sciurba
authors.forename: James P
authors.initials: JP
authors.lastname: Utz
authors.forename: John J
authors.initials: JJ
authors.lastname: Reilly
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
mesh_terms: D000368:Aged; D004851:Epoxide Hydrolases / Q000235:genetics; D017079:Exercise Tolerance / Q000235:genetics*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D053779:Latent TGF-beta Binding Proteins; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000503:physiopathology*; D037701:Pulmonary Surfactant-Associated Protein B / Q000235:genetics; D012129:Respiratory Function Tests; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C509040:LTBP4 protein, human; D053779:Latent TGF-beta Binding Proteins; D037701:Pulmonary Surfactant-Associated Protein B; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D004851:Epoxide Hydrolases