Epigenome-wide analysis identifies pollution-sensitive loci in fibrotic interstitial lung disease

Rationale: Particulate matter <=2.5um (PM2.5) adversely impacts patients with fibrotic interstitial lung disease (fILD). Objective: To determine whether PM2.5-associated epigenetic alterations contribute to the environmental pathogenesis of fILD.Methods: Retrospective two-cohort study applying satellite-derived PM2.5 and constituent exposure matching to the residential location of patients with fILD. Robust linear regressions evaluated cohort-specific epigenome-wide differential blood DNA methylation with increasing pollutant exposures (Illumina MethylationEPIC BeadChip). Cox and linear regressions evaluated associations of cytosine-phosphate-guanine (CpG) loci with transplant-free survival and lung function. Wilcoxon test evaluated cartilage-associated protein (CRTAP) levels in fILD and control lungs.Results: The University of Pittsburgh (UPitt) cohort (n=306) had 5-year median PM2.5 exposures of 12.1ug/m3 compared with 5.1ug/m3 in the University of British Columbia (UBC) cohort (n=170). Higher pollutant exposures in the UPitt cohort were associated with lower methylation at cg25354716, annotated to CRTAP, a critical extracellular matrix remodeling enzyme. Higher exposures in the UBC cohort were associated with higher methylation at cg01019301, annotated to TLN2 (talin-2), a cytoskeletal protein involved in fibroblast migration. A 10% increase in cg25354716 methylation was associated with a hazard ratio (HR) of 0.81 for death or lung transplantation in the meta-analyzed cohorts (95%CI 0.69-0.96, p=0.01), whereas the same change in cg01019301 was associated with a HR of 1.36 (95%CI 1.07-1.74, p=0.01). CRTAP protein was overexpressed more abundant in lungs tissue from patients with fILD compared with donor controls (p<0.001). Conclusions: PM2.5 is associated with altered blood DNA methylation in fILD. This work identifies novel pollution-sensitive targets that hold potential for therapeutic modulation in fILD. We aimed to profile the blood DNA methylation profile (Illumina MethylationEPIC BeadChip Array) from patients with various forms of fibrotic interstitial lung disease and match that with satellite-derived hybrid model estimates of PM2.5 and constituent components (pollutant data accessed from the Atmospheric Composition Analysis Group online repository: https://sites.wustl.edu/acag/datasets/surface-pm2-5/) to the residential location of these patients. Epigenome-wide association of PM2.5 and constituent exposures with differential methylation was then performed. The analysis cohort included 306 patients with fILD from the University of Pittsburgh Simmons Center for Interstitial Lung Disease cohort and 170 from the University of British Columbia ILD Registry. There was one duplicate sample removed from this dataset (patient 199) and three samples that were excluded from the analysis due to quality issues.