RATIONALE: Patients with severe chronic obstructive pulmonary disease (COPD) may have varying levels of disability despite similar levels of lung function. This variation may reflect different COPD subtypes, which may have different genetic predispositions. OBJECTIVES: To identify genetic associations for COPD-related phenotypes, including measures of exercise capacity, pulmonary function, and respiratory symptoms. METHODS: In 304 subjects from the National Emphysema Treatment Trial, we genotyped 80 markers in 22 positional and/or biologically plausible candidate genes. Regression models were used to test for association, using a test-replication approach to guard against false-positive results. For significant associations, effect estimates were recalculated using the entire cohort. Positive associations with dyspnea were confirmed in families from the Boston Early-Onset COPD Study. RESULTS: The test-replication approach identified four genes-microsomal epoxide hydrolase (EPHX1), latent transforming growth factor-beta binding protein-4 (LTBP4), surfactant protein B (SFTPB), and transforming growth factor-beta1 (TGFB1)-that were associated with COPD-related phenotypes. In all subjects, single-nucleotide polymorphisms (SNPs) in EPHX1 (p < or = 0.03) and in LTBP4 (p < or = 0.03) were associated with maximal output on cardiopulmonary exercise testing. Markers in LTBP4 (p < or = 0.05) and SFTPB (p = 0.005) were associated with 6-min walk test distance. SNPs in EPHX1 were associated with carbon monoxide diffusing capacity (p < or = 0.04). Three SNPs in TGFB1 were associated with dyspnea (p < or = 0.002), one of which replicated in the family study (p = 0.02). CONCLUSIONS: Polymorphisms in several genes seem to be associated with COPD-related traits other than FEV(1). These associations may identify genes in pathways important for COPD pathogenesis.
RATIONALE: Patients with severe chronic obstructive pulmonary disease (COPD) may have varying levels of disability despite similar levels of lung function. This variation may reflect different COPD subtypes, which may have different genetic predispositions. OBJECTIVES: To identify genetic associations for COPD-related phenotypes, including measures of exercise capacity, pulmonary function, and respiratory symptoms. METHODS: In 304 subjects from the National Emphysema Treatment Trial, we genotyped 80 markers in 22 positional and/or biologically plausible candidate genes. Regression models were used to test for association, using a test-replication approach to guard against false-positive results. For significant associations, effect estimates were recalculated using the entire cohort. Positive associations with dyspnea were confirmed in families from the Boston Early-Onset COPD Study. RESULTS: The test-replication approach identified four genes-microsomal epoxide hydrolase (EPHX1), latent transforming growth factor-beta binding protein-4 (LTBP4), surfactant protein B (SFTPB), and transforming growth factor-beta1 (TGFB1)-that were associated with COPD-related phenotypes. In all subjects, single-nucleotide polymorphisms (SNPs) in EPHX1 (p < or = 0.03) and in LTBP4 (p < or = 0.03) were associated with maximal output on cardiopulmonary exercise testing. Markers in LTBP4 (p < or = 0.05) and SFTPB (p = 0.005) were associated with 6-min walk test distance. SNPs in EPHX1 were associated with carbon monoxide diffusing capacity (p < or = 0.04). Three SNPs in TGFB1 were associated with dyspnea (p < or = 0.002), one of which replicated in the family study (p = 0.02). CONCLUSIONS: Polymorphisms in several genes seem to be associated with COPD-related traits other than FEV(1). These associations may identify genes in pathways important for COPD pathogenesis.
Authors: Craig P Hersh; Dawn L Demeo; Christoph Lange; Augusto A Litonjua; John J Reilly; David Kwiatkowski; Nan Laird; Jody S Sylvia; David Sparrow; Frank E Speizer; Scott T Weiss; Edwin K Silverman Journal: Am J Respir Cell Mol Biol Date: 2005-04-07 Impact factor: 6.914
Authors: Dawn L Demeo; Thomas J Mariani; Christoph Lange; Sorachai Srisuma; Augusto A Litonjua; Juan C Celedon; Stephen L Lake; John J Reilly; Harold A Chapman; Brigham H Mecham; Kathleen J Haley; Jody S Sylvia; David Sparrow; Avrum E Spira; Jennifer Beane; Victor Pinto-Plata; Frank E Speizer; Steven D Shapiro; Scott T Weiss; Edwin K Silverman Journal: Am J Hum Genet Date: 2005-12-15 Impact factor: 11.025
Authors: Bartolome R Celli; Claudia G Cote; Jose M Marin; Ciro Casanova; Maria Montes de Oca; Reina A Mendez; Victor Pinto Plata; Howard J Cabral Journal: N Engl J Med Date: 2004-03-04 Impact factor: 91.245
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Authors: Michael H Cho; George R Washko; Thomas J Hoffmann; Gerard J Criner; Eric A Hoffman; Fernando J Martinez; Nan Laird; John J Reilly; Edwin K Silverman Journal: Respir Res Date: 2010-03-16
Authors: Jessica M Bon; Joseph K Leader; Joel L Weissfeld; Harvey O Coxson; Bin Zheng; Robert A Branch; Venkateswarlu Kondragunta; Janet S Lee; Yingze Zhang; Augustine M K Choi; Anna E Lokshin; Naftali Kaminski; David Gur; Frank C Sciurba Journal: PLoS One Date: 2009-08-31 Impact factor: 3.240
Authors: Ceri E Stewart; Ian P Hall; Stuart G Parker; Miriam F Moffat; Andrew J Wardlaw; Martin J Connolly; Charlotte Ruse; Ian Sayers Journal: BMC Med Genet Date: 2009-10-31 Impact factor: 2.103