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

Weiliang Qiu, Andrea Baccarelli, Vincent J. Carey, Nadia Boutaoui, Helene Bacherman, Barbara Klanderman, Stephen Rennard, Alvar Agusti, Wayne Anderson, David A. Lomas, Dawn L. DeMeo

Research output: Contribution to journalArticlepeer-review

140 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)373-381
Number of pages9
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume185
Issue number4
DOIs
StatePublished - Feb 15 2012

Keywords

  • Chronic obstructive pulmonary disease
  • DNA methylation
  • Epigenetics
  • Smoking

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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