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Genetic Determinants of Emphysema Distribution in the National Emphysema Treatment Trial

¹ Channing Laboratory and ² Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; ³ University of Iowa, Iowa City, Iowa; ⁴ Veterans Affairs Medical Center and the Pulmonary Center, Boston University, Boston, Massachusetts; ⁵ University of Washington, Seattle, Washington; ⁶ Temple University, Philadelphia, Pennsylvania; ⁷ National Jewish Medical and Research Center, Denver, Colorado; ⁸ University of Michigan, Ann Arbor, Michigan; ⁹ Mayo Clinic, Rochester, Minnesota; and ¹⁰ University of Pittsburgh, Pittsburgh, Pennsylvania

Correspondence and requests for reprints should be sent to Dawn L. DeMeo, M.D., M.P.H., Brigham and Women's Hospital, Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115. E-mail: dawn.demeo{at}channing.harvard.edu

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 ₁-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.

Key Words: COPD • genetics • association analysis • computed tomography • emphysema

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject There are few studies regarding the genetic factors that may determine emphysema distribution. Computed tomography scanning may reduce phenotypic heterogeneity in chronic obstructive pulmonary disease genetic studies, and allow identification of genetic determinants of emphysema severity and distribution. What This Study Adds to the Field This study identifies genes encoding xenobiotic enzymes as differentially associated with distributional features of emphysema. Altered detoxification of cigarette smoke metabolites may contribute to emphysema distribution.

 

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