Genetic determinants of emphysema distribution in the national emphysema treatment trial.
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.
DeMeo
Dawn L
DL
Channing Laboratory, Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. dawn.demeo@channing.harvard.edu
Hersh
Craig P
CP
Hoffman
Eric A
EA
Litonjua
Augusto A
AA
Lazarus
Ross
R
Sparrow
David
D
Benditt
Joshua O
JO
Criner
Gerard
G
Make
Barry
B
Martinez
Fernando J
FJ
Scanlon
Paul D
PD
Sciurba
Frank C
FC
Utz
James P
JP
Reilly
John J
JJ
Silverman
Edwin K
EK
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
D051549:Glutathione S-Transferase pi; D004851:Epoxide Hydrolases; C522330:EPHX1 protein, human