Variable DNA methylation is associated with chronic obstructive pulmonary disease and lung function

Am J Respir Crit Care Med. 2012 Feb 15;185(4):373-81. doi: 10.1164/rccm.201108-1382OC. Epub 2011 Dec 8.

Abstract

Rationale: 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.

Objectives: 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).

Measurements and main 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cohort Studies
  • CpG Islands / genetics
  • DNA Methylation*
  • Epigenesis, Genetic*
  • Female
  • Forced Expiratory Volume
  • Genetic Markers
  • Genetic Predisposition to Disease
  • Humans
  • Linear Models
  • Male
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • Pulmonary Disease, Chronic Obstructive / genetics*
  • Pulmonary Disease, Chronic Obstructive / physiopathology
  • Smoking / adverse effects
  • Vital Capacity
  • alpha 1-Antitrypsin / genetics

Substances

  • Genetic Markers
  • SERPINA1 protein, human
  • alpha 1-Antitrypsin