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Published ahead of print on March 15, 2007, doi:10.1164/rccm.200612-1797OC

Am. J. Respir. Crit. Care Med., Volume 176, Number 1, July 2007, 42-48

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Submitted on December 12, 2006
Accepted on March 15, 2007

Genetic Determinants of Emphysema Distribution in the National Emphysema Treatment Trial

Dawn L DeMeo1*, Craig P Hersh1, Eric A Hoffman2, Augusto A Litonjua1, Ross Lazarus1, David Sparrow3, Joshua O Benditt4, Gerard Criner5, Barry Make6, Fernando J Martinez7, Paul D Scanlon8, Frank C Sciurba9, James P Utz8, John J Reilly10, and Edwin K Silverman1

1 Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA, 2 University of Iowa, Iowa City, IA, USA, 3 Veterans Affairs Medical Center and The Pulmonary Center, Boston University, Boston, MA, USA, 4 University of Washington, Seattle, WA, USA, 5 Temple University, Philadelphia, PA, USA, 6 National Jewish Medical and Research Center, Denver, CO, USA, 7 University of Michigan, Ann Arbor, MI, USA, 8 Mayo Clinic, Rochester, MN, USA, 9 University of Pittsburgh, Pittsburgh, PA, USA, 10 Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

* To whom correspondence should be addressed. E-mail: dawn.demeo{at}channing.harvard.edu.

Objective: CT scanning of the lung may reduce phenotypic heterogeneity in defining subjects with COPD, and allow identification of genetic determinants of emphysema severity and distribution. We sought to identify genes associated with CT scan distribution of emphysema in individuals without alpha 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 (NETT), and used regression models to identify genetic variants associated with emphysema distribution. Main outcome measures: Emphysema distribution was assessed by two methods-assessment by radiologists and by computerized density mask quantitation, using a threshold of -950 Hounsfield units. Seventy seven polymorphisms in 20 candidate genes were analyzed for association with distribution of emphysema. Results: GSTP1, EPHX1 and MMP1 polymorphisms were associated with the densitometric apical predominant distribution of emphysema (p range=0.001-0.05). When an apical predominant phenotype was defined by the radiologist scoring method, GSTP1 and EPHX1 SNPs 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 SNP His139Arg 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,CT scan, emphysema, GSTP1




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