Epigenome-Wide Association Studies of Chronic Obstructive Pulmonary Disease and Lung Function: A Systematic Review

Rationale: Chronic obstructive pulmonary disease (COPD) results from gene-environment interactions over the lifetime. These interactions are captured by epigenetic changes, such as DNA methylation. Objectives: To systematically review the evidence form epigenome-wide association studies related to COPD and lung function. Methods: A systematic literature search performed on PubMed, Embase, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases identified 1,947 articles that investigated epigenetic changes associated with COPD and/or lung function; 17 of them met our eligibility criteria, from which data were manually extracted. Differentially methylated positions (DMPs) and/or annotated genes were considered replicated if identified by two or more studies with a P < 1 × 10-4. Measurements and Main Results: Ten studies profiled DNA methylation changes in blood and seven in respiratory samples, including surgically resected lung tissue (n = 3), small airway epithelial brushings (n = 2), BAL (n = 1), and sputum (n = 1). Main results showed: 1) high variability in study design, covariates, and effect sizes, which prevented a formal meta-analysis; 2) in blood samples, 51 DMPs were replicated in relation to lung function and 12 related to COPD; 3) in respiratory samples, 42 DMPs were replicated in relation to COPD but none in relation to lung function; and 4) in COPD versus control studies, 123 genes (2.6% of total) were shared between one or more blood and one or more respiratory samples and associated with chronic inflammation, ion transport, and coagulation. Conclusions: There is high heterogeneity across published COPD and/or lung function epigenome-wide association studies. A few genes (n = 123; 2.6%) were replicated in blood and respiratory samples, suggesting that blood can recapitulate some changes in respiratory tissues. These findings have implications for future research. Systematic Review [protocol] registered with Open Science Framework (OSF).