PM_2.5 and constituent component impacts on global DNA methylation in patients with idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease (ILD) whose outcomes are worsened with air pollution exposures. DNA methylation (DNAm) patterns are altered in lungs and blood from patients with IPF, but the relationship between air pollution exposures and DNAm patterns in IPF remains unexplored. This study aimed to evaluate the association of PM_2.5 and constituent components with global DNAm in patients with IPF. Patients enrolled in either the University of Pittsburgh Simmons Center for ILD Registry (Simmons) or the U.S.-wide Pulmonary Fibrosis Foundation (PFF) Patient Registry with peripheral blood DNA samples were included. The averages of monthly exposures to PM_2.5 and constituents over 1-year and 3-months pre-blood collection were matched to patient residential coordinates using satellite-derived hybrid models. Global DNAm percentage (%5 mC) was determined using the ELISA-based MethylFlash assay. Associations of pollutants with %5 mC were assessed using beta-regression, Cox models for mortality, and linear regression for baseline lung function. Mediation proportion was determined for models where pollutant-mortality and pollutant-%5 mC associations were significant. Inclusion criteria were met by 313 Simmons and 746 PFF patients with IPF. Higher PM_2.5 3-month exposures prior to blood collection were associated with higher %5 mC in Simmons (β = 0.02, 95%CI 0.0003-0.05, p = 0.047), with trends in the same direction in the 1-year period in both cohorts. Higher exposures to sulfate, nitrate, ammonium, and black carbon constituents were associated with higher %5 mC in multiple models. Percent 5 mC was not associated with IPF mortality or lung function, but was found to mediate between 2 and 5% of the associations of PM_2.5, sulfate, and ammonium with mortality. In conclusion, we found that higher global DNAm is a novel biomarker for increased PM_2.5 and anthropogenic constituent exposure in patients with IPF. Mechanistic research is needed to determine if DNAm has pathogenic relevance in mediating associations between pollutants and mortality in IPF.