title: DNA methylation profiling in human lung tissue identifies genes associated with COPD.
abstract: Chronic obstructive pulmonary disease (COPD) is a smoking-related disease characterized by genetic and phenotypic heterogeneity. Although association studies have identified multiple genomic regions with replicated associations to COPD, genetic variation only partially explains the susceptibility to lung disease, and suggests the relevance of epigenetic investigations. We performed genome-wide DNA methylation profiling in homogenized lung tissue samples from 46 control subjects with normal lung function and 114 subjects with COPD, all former smokers. The differentially methylated loci were integrated with previous genome-wide association study results. The top 535 differentially methylated sites, filtered for a minimum mean methylation difference of 5% between cases and controls, were enriched for CpG shelves and shores. Pathway analysis revealed enrichment for transcription factors. The top differentially methylated sites from the intersection with previous GWAS were in CHRM1, GLT1D1, and C10orf11; sorted by GWAS P-value, the top sites included FRMD4A, THSD4, and C10orf11. Epigenetic association studies complement genetic association studies to identify genes potentially involved in COPD pathogenesis. Enrichment for genes implicated in asthma and lung function and for transcription factors suggests the potential pathogenic relevance of genes identified through differential methylation and the intersection with a broader range of GWAS associations.
authors: a Channing Division of Network Medicine, Brigham and Women's Hospital , Boston , MA , USA.
authors: Jarrett D
authors: JD
authors: Morrow
authors: a Channing Division of Network Medicine, Brigham and Women's Hospital , Boston , MA , USA.|b Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital , Boston , MA , USA.
authors: Michael H
authors: MH
authors: Cho
authors: a Channing Division of Network Medicine, Brigham and Women's Hospital , Boston , MA , USA.|b Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital , Boston , MA , USA.
authors: Craig P
authors: CP
authors: Hersh
authors: c Baystate Health , Springfield , MA , USA.
authors: Victor
authors: V
authors: Pinto-Plata
authors: b Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital , Boston , MA , USA.
authors: Bartolome
authors: B
authors: Celli
authors: d Division of Pulmonary and Critical Care Medicine, Temple University , Philadelphia , PA , USA.
authors: Nathaniel
authors: N
authors: Marchetti
authors: d Division of Pulmonary and Critical Care Medicine, Temple University , Philadelphia , PA , USA.
authors: Gerard
authors: G
authors: Criner
authors: e Division of Thoracic Surgery, Brigham and Women's Hospital , Boston , MA , USA.
authors: Raphael
authors: R
authors: Bueno
authors: b Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital , Boston , MA , USA.
authors: George
authors: G
authors: Washko
authors: a Channing Division of Network Medicine, Brigham and Women's Hospital , Boston , MA , USA.
authors: Kimberly
authors: K
authors: Glass
authors: f Department of Medicine , New York Presbyterian/Weill Cornell Medical Center , New York , NY , USA.
authors: Augustine M K
authors: AMK
authors: Choi
authors: g Department of Biostatistics and Computational Biology , Dana-Farber Cancer Institute , Boston , MA , USA.
authors: John
authors: J
authors: Quackenbush
authors: a Channing Division of Network Medicine, Brigham and Women's Hospital , Boston , MA , USA.|b Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital , Boston , MA , USA.
authors: Edwin K
authors: EK
authors: Silverman
authors: a Channing Division of Network Medicine, Brigham and Women's Hospital , Boston , MA , USA.|b Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital , Boston , MA , USA.
authors: Dawn L
authors: DL
authors: DeMeo
keywords: Chronic obstructive pulmonary disease; DNA methylation profiling; epigenetics