Blood DNA methylation profiling identified 1,177 CpGs (without FEV1 adjustment) and 343 CpGs (with FEV1 adjustment) associated with CT-quantified emphysema severity.
Observational (n=5,433)
Blood DNA methylation profiles reflect systemic molecular changes associated with emphysema severity, highlighting pathways involved in tissue injury and remodeling independent of airflow limitation.
Abstract Background Emphysema, a defining feature of chronic obstructive pulmonary disease (COPD), exhibits marked inter-individual variability. DNA methylation may capture molecular regulation associated with structural lung destruction beyond spirometric impairment. Objectives To identify blood-based methylation signatures associated with CT-quantified emphysema, measured as volume-adjusted 15th percentile of lung attenuation (Perc15), and evaluate their biological relevance in COPD. Methods Whole-blood DNA methylation was profiled using the Illumina EPIC platform in 5,433 COPDGene Phase 2 participants. After quality control and normalization, epigenome-wide association analyses (EWAS) were conducted with Perc15 as a continuous outcome, controlling for demographic, smoking, cellular heterogeneity, and technical factors, with and without FEV1. Test statistics were corrected for inflation using the Bayesian Adjustment for Confounding (BACON) method. Significant CpG sites (FDR 0.05) were annotated to nearest genes (hg19) and assessed for Gene Ontology pathway enrichment. Differentially methylated regions (DMRs) were identified by aggregating CpG-level signals within genomic regions. Sensitivity analyses evaluated consistency of associations across race, sex, and smoking strata. Results A total of 1,177 CpGs (without FEV1 adjustment) and 343 CpGs (with FEV1 adjustment) were associated with emphysema. Leading signals without FEV1 adjustment included PRSS23, ABCG1, AHRR, and MGAT3; models including FEV1 highlighted ABCG1, DHCR24, DSE, and LOC100996291, indicating both shared and distinct methylation signatures independent of airflow limitation. DMR analysis identified 118 regions (without FEV1 adjustment) and 604 (with FEV1 adjustment), with 328 overlapping and 151 exact matches between models. These CpGs mapped to genes involved in lipid metabolism, oxidative stress, and inflammatory signaling. Sensitivity analyses demonstrated consistent associations across race, sex, and smoking groups. Conclusion Blood DNA methylation profiles reflect systemic molecular changes associated with emphysema severity, highlighting pathways involved in tissue injury and remodeling. Future studies will validate these findings in independent cohorts and integrate methylation withmulti-omics data to advance mechanistic understanding and biomarker discovery. This abstract is funded by: This work was supported by NHLBI R01HL178032, R01HL167072, R01HL124233, R01HL166992, and R01HL171213. The COPDGene study (NCT00608764) is supported by grants from the NHLBI (U01HL089897 and U01HL089856), by NIH contract 75N92023D00011, and by the COPD Foundation through contributions made to an Industry Advisory Committee that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion. Molecular data from the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI).
Fordel et al. (Fri,) conducted a observational in Emphysema in chronic obstructive pulmonary disease (COPD) (n=5,433). Blood DNA methylation profiling was evaluated on CT-quantified emphysema, measured as volume-adjusted 15th percentile of lung attenuation (Perc15). Blood DNA methylation profiling identified 1,177 CpGs (without FEV1 adjustment) and 343 CpGs (with FEV1 adjustment) associated with CT-quantified emphysema severity.