Abstract Rationale Circulating cell-free DNA (ccfDNA) reflects ongoing tissue damage and remodeling dynamic processes, and has emerged as a promising minimally invasive biomarker for chronic obstructive lung disease (COPD). We have previously shown that specific epigenetic signatures can distinguish COPD and predict lung function in former smokers with high accuracy (AUC 0. 96) with high sensitivity (0. 93) and specificity (0. 85). However, its epigenetic landscape and its potential to capture disease heterogeneity and progression in COPD remain largely unexplored. Based on large-scale ccfDNA profiles, we aimed to identify epigenetically regulated pathways that identify COPD progression patterns as related to differential lung function trajectories. Methods COPD patients were followed over 10 years with post-bronchodilator spirometry at 3 timepoints. Fast lung function decline was defined as FEV1 loss 30 mL/year. Blood samples were collected at V2. Plasma ccfDNA methylation profiles were assessed by whole-genome bisulfite sequencing (WGBS). Differentially methylated loci (DML; Fold Changes2, adjusted p 0. 05) were identified and mapped to their corresponding genes. Pathway enrichment was performed using GSEApy and Biomart tools based upon GO (BP), KEGG and Reactome databases, with a significance threshold FDR0. 05. Results COPD patients were stratified into stable (SD-COPD; n = 13), fast declining (FD-COPD; n = 13) trajectories and into smokers without COPD and stable lung function (SC; n = 12). Compared to the SC group, 633, 554 and 725, 309 DMLs emerged for the SD-COPD and FD-COPD groups, respectively. Pathway and network analyses revealed a core COPD signature enriched for tissue morphogenesis and cell architecture terms (e. g. , developmental process, p = 2. 69x10-6; system development, p = 1. 13x10-5; cell junction, p = 3. 89x10-4; cell projection, p = 1. 13x10-4; synapse, p = 4. 80x10-3), consistent with structural remodeling and neuro-epithelial crosstalk. Beyond this shared axis, FD-COPD showed a postsynaptic-focused enrichment (e. g. , postsynaptic membrane, p = 3. 14x10-5; neuronal system, p = 0. 032), while SD-COPD was enriched for neurodevelopmental programs (axon guidance, p = 2. 77x10-3; neurogenesis, p = 3. 48x10-5), suggesting adaptive wiring in stable disease versus maladaptive synaptic remodeling in fast declining COPD. Conclusions This study provides evidence of epigenetic dysregulation associated with COPD progression that can be detected on ccfDNA samples. Shared methylation patterns reflect persistent structural and neuro-epithelial remodeling, while specific synaptic pathways characterize patients with accelerated functional decline. Thus, ccfDNA methylation provides a non-invasive molecular readout of COPD pathobiology and a promising tool for monitoring disease trajectories and therapeutic responses. This abstract is funded by: Startup grant from the University of Missouri to RC, Instituto Salud Carlos III (CD22/00033 and MV23/00010) and Government of Aragon (CUS/1638/2022; B22₂3R)
Rubio et al. (Fri,) studied this question.