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

Abstract

<b>Rationale:</b> Chronic obstructive pulmonary disease (COPD) results from gene-environment interactions over the lifetime. These interactions are captured by epigenetic changes, such as DNA methylation. <b>Objectives:</b> To systematically review the evidence form epigenome-wide association studies related to COPD and lung function. <b>Methods:</b> 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 <i>P</i> < 1 × 10^-4. <b>Measurements and Main Results:</b> Ten studies profiled DNA methylation changes in blood and seven in respiratory samples, including surgically resected lung tissue (<i>n</i> = 3), small airway epithelial brushings (<i>n</i> = 2), BAL (<i>n</i> = 1), and sputum (<i>n</i> = 1). Main results showed: <i>1</i>) high variability in study design, covariates, and effect sizes, which prevented a formal meta-analysis; <i>2</i>) in blood samples, 51 DMPs were replicated in relation to lung function and 12 related to COPD; <i>3</i>) in respiratory samples, 42 DMPs were replicated in relation to COPD but none in relation to lung function; and <i>4</i>) 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. <b>Conclusions:</b> There is high heterogeneity across published COPD and/or lung function epigenome-wide association studies. A few genes (<i>n</i> = 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).