title: Genetic determinants of emphysema distribution in the national emphysema treatment trial.
abstract: BACKGROUND
  Computed tomography (CT) scanning of the lung may reduce phenotypic heterogeneity in defining subjects with chronic obstructive pulmonary disease (COPD), and allow identification of genetic determinants of emphysema severity and distribution.
  
  
  OBJECTIVE
  We sought to identify genes associated with CT scan distribution of emphysema in individuals without alpha1-antitrypsin deficiency but with severe COPD.
  
  
  METHODS
  We evaluated baseline CT densitometry phenotypes in 282 individuals with emphysema enrolled in the Genetics Ancillary Study of the National Emphysema Treatment Trial, and used regression models to identify genetic variants associated with emphysema distribution.
  
  
  RESULTS
  Emphysema distribution was assessed by two methods--assessment by radiologists and by computerized density mask quantitation, using a threshold of -950 Hounsfield units. A total of 77 polymorphisms in 20 candidate genes were analyzed for association with distribution of emphysema. GSTP1, EPHX1, and MMP1 polymorphisms were associated with the densitometric, apical-predominant distribution of emphysema (p value range = 0.001-0.050). When an apical-predominant phenotype was defined by the radiologist scoring method, GSTP1 and EPHX1 single-nucleotide polymorphisms were found to be significantly associated. In a case-control analysis of COPD susceptibility limited to cases with densitometric upper-lobe-predominant cases, the EPHX1 His139Arg single-nucleotide polymorphism was associated with COPD (p = 0.005).
  
  
  CONCLUSIONS
  Apical and basal emphysematous destruction appears to be influenced by different genes. Polymorphisms in the xenobiotic enzymes, GSTP1 and EPHX1, are associated with apical-predominant emphysema. Altered detoxification of cigarette smoke metabolites may contribute to emphysema distribution, and these findings may lead to further insight into genetic determinants of emphysema.
authors.affiliation: Channing Laboratory, Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. dawn.demeo@channing.harvard.edu
authors.forename: Dawn L
authors.initials: DL
authors.lastname: DeMeo
authors.forename: Craig P
authors.initials: CP
authors.lastname: Hersh
authors.forename: Eric A
authors.initials: EA
authors.lastname: Hoffman
authors.forename: Augusto A
authors.initials: AA
authors.lastname: Litonjua
authors.forename: Ross
authors.initials: R
authors.lastname: Lazarus
authors.forename: David
authors.initials: D
authors.lastname: Sparrow
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: D015502:Absorptiometry, Photon; D000368:Aged; D016022:Case-Control Studies; D015331:Cohort Studies; D004646:Emphysema / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D004851:Epoxide Hydrolases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D012907:Smoking / Q000009:adverse effects; D014057:Tomography, X-Ray Computed
chemical_list: D051549:Glutathione S-Transferase pi; D004851:Epoxide Hydrolases; C522330:EPHX1 protein, human