Journal
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Volume 185, Issue 4, Pages 373-381Publisher
AMER THORACIC SOC
DOI: 10.1164/rccm.201108-1382OC
Keywords
chronic obstructive pulmonary disease; epigenetics; DNA methylation; smoking
Categories
Funding
- U.S. National Institutes of Health [R01 HL089438]
- Doris Duke Foundation
- GlaxoSmithKline
- ES00002 New Investigator Funding
- [P01 HL105339]
- MRC [G0901786] Funding Source: UKRI
- Medical Research Council [G0901786] Funding Source: researchfish
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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 x 10(-23); FEV1/FVC, 1.5 x 10(-35); FEV1, 2.2 x 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.
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