title: Variable DNA methylation is associated with chronic obstructive pulmonary disease and lung function.
abstract: BACKGROUND
  Chronic obstructive pulmonary disease (COPD) is associated with local (lung) and systemic (blood) inflammation and manifestations. DNA methylation is an important regulator of gene transcription, and global and specific gene methylation marks may vary with cigarette smoke exposure.
  
  
  OBJECTIVE
  To perform a comprehensive assessment of methylation marks in DNA from subjects well phenotyped for nonneoplastic lung disease.
  
  
  METHODS
  We conducted array-based methylation screens, using a test-replication approach, in two family-based cohorts (n = 1,085 and 369 subjects).
  
  
  RESULTS
  We observed 349 CpG sites significantly associated with the presence and severity of COPD in both cohorts. Seventy percent of the associated CpG sites were outside of CpG islands, with the majority of CpG sites relatively hypomethylated. Gene ontology analysis based on these 349 CpGs (330 genes) suggested the involvement of a number of genes responsible for immune and inflammatory system pathways, responses to stress and external stimuli, as well as wound healing and coagulation cascades. Interestingly, our observations include significant, replicable associations between SERPINA1 hypomethylation and COPD and lower average lung function phenotypes (combined P values: COPD, 1.5 × 10(-23); FEV(1)/FVC, 1.5 × 10(-35); FEV(1), 2.2 × 10(-40)).
  
  
  CONCLUSIONS
  Genetic and epigenetic pathways may both contribute to COPD. Many of the top associations between COPD and DNA methylation occur in biologically plausible pathways. This large-scale analysis suggests that DNA methylation may be a biomarker of COPD and may highlight new pathways of COPD pathogenesis.
authors.affiliation: Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Qiu
authors.forename: Andrea
authors.initials: A
authors.lastname: Baccarelli
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Carey
authors.forename: Nadia
authors.initials: N
authors.lastname: Boutaoui
authors.forename: Helene
authors.initials: H
authors.lastname: Bacherman
authors.forename: Barbara
authors.initials: B
authors.lastname: Klanderman
authors.forename: Stephen
authors.initials: S
authors.lastname: Rennard
authors.forename: Alvar
authors.initials: A
authors.lastname: Agusti
authors.forename: Wayne
authors.initials: W
authors.lastname: Anderson
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.forename: Dawn L
authors.initials: DL
authors.lastname: DeMeo
mesh_terms: D015331:Cohort Studies; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005541:Forced Expiratory Volume; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000503:physiopathology; D012907:Smoking / Q000009:adverse effects; D014797:Vital Capacity; D000515:alpha 1-Antitrypsin / Q000235:genetics
chemical_list: D005819:Genetic Markers; C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin