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Genetic Determinants of Emphysema Distribution in the National Emphysema Treatment Trial

Year: 2007
Type: article
Abstract: RATIONALE: 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. OBJECTIVES: 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. MEASUREMENTS AND MAIN 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.
DOI: 10.1164/rccm.200612-1797oc
Authors: Dawn L. DeMeo, Craig P. Hersh, Eric A. Hoffman, Augusto A. Litonjua, Ross Lazarus, David Sparrow, 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
Institutions: Brigham and Women's Hospital, Harvard University, University of Iowa, Boston University, University of Washington, Temple University, National Jewish Health, University of Michigan, Mayo Clinic, University of Pittsburgh
Language: English
Field: Medicine
Open Access status: green
Awards: CLINICAL CENTER FOR THE LUNG VOLUME REDUCTION SURGERY, G1207659464, G1220799682, LUNG VOLUME REDUCTION STUDY--CLINICAL CENTER, G1439225947, G1576662596, G1615620936, CLINICAL CENTER FOR LVRS, G1735610881, CLNICAL CENTER FOR LVRS, CLNICAL CENTER FOR LVRS, G182694510, LUNG VOLUME REDUCTION STUDY--CLINICAL CENTER, LUNG VOLUME REDUCTION SURGERY--CLINICAL CENTER, LUNG VOLUME REDUCTION SURGERY--CLINICAL CENTER, G2412257637, LUNG VOLUME REDUCTION SURGERY--CLINICAL CENTER, LUNG VOLUME REDUCTION SURGERY--CLINICAL CENTER, G2599011918, G278468722, G3110798224, CLINICAL COORDINATING CENTER FOR LVRS, G3805264881, G4153249725, G4255341634, Genetics of COPD in NETT, Fine Mapping of COPD Susceptibility Genes, G48533833, G556935766, G6315211796, CLNICAL CENTER FOR THE LVRS, LUNG VOLUME REDUCTION SURGERY--CLINICAL CENTER, CLINICAL CENTER FOR LVRS, CLINICAL CENTER FOR THE LUNG VOLUME REDUCTION SURGERY, G778147052, Asthma Candidate Genes in Alpha 1-Antitrypsin Deficiency, LUNG VOLUME REDUCTION SURGERY--CLINICAL CENTER, CLINICAL CENTER FOR THE LUNG VOLUME REDUCTION SURGERY, CLINICAL CENTER FOR THE LUNG VOLUME REDUCTION SURGERY
OpenAlex ID: W2015867310
FWCI: 18.44
Cites: 35
Cited by: 145
Related to: 10