Genetic Determinants of Emphysema Distribution in the National Emphysema Treatment Trial
Dawn L. DeMeo,Craig P. Hersh,Eric A. Hoffman,Augusto A. Litonjua,Ross Lazarus,David Sparrow,Joshua O. Benditt,Gerard J. Criner,Barry Make,Fernando J. Martinez,Paul D. Scanlon,Frank C. Sciurba,James P. Utz,John J. Reilly,Edwin K. Silverman +14 more
TLDR
Polymorphisms in the xenobiotic enzymes, GSTP1 and EPHX1, are associated with apical-predominant emphysema, and these findings may lead to further insight into genetic determinants of emphySEma.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 α1-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.read more
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Genetic Epidemiology of COPD (COPDGene) Study Design
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TL;DR: CPDGene will provide important new information about genetic factors in COPD, and will characterize the disease process using high resolution CT scans, which will potentially permit earlier diagnosis of this disease and may lead to the development of treatments to modify progression.
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TL;DR: A number of studies have shown that there is no single "magic bullet" to combat oxidative stress, but instead a combination therapy, targeting oxidative stress in the various subcellular compartments, may prove to be more effective in COPD.
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Mechanisms of cigarette smoke-induced COPD: insights from animal models.
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Pathogenic triad in COPD: oxidative stress, protease-antiprotease imbalance, and inflammation.
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The presence and progression of emphysema in COPD as determined by CT scanning and biomarker expression: a prospective analysis from the ECLIPSE study
Harvey O. Coxson,Asger Dirksen,Lisa D. Edwards,Julie C. Yates,Alvar Agusti,Per Bakke,Peter M.A. Calverley,Bartolome R. Celli,Courtney Crim,Annelyse Duvoix,Paola V. Nasute Fauerbach,David A. Lomas,William MacNee,Ruth J. Mayer,Bruce E. Miller,Nestor L. Müller,Stephen I. Rennard,Edwin K. Silverman,Ruth Tal-Singer,Emiel F.M. Wouters,Jørgen Vestbo,Jørgen Vestbo +21 more
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