Epigenome-Wide Analysis Identifies Pollution-Sensitive Loci in Fibrotic Interstitial Lung Disease

Rationale: Particulate matter ⩽2.5 μm (PM_2.5) adversely impacts patients with fibrotic interstitial lung disease (fILD). Objectives: We sought to determine whether PM_2.5-associated epigenetic alterations contribute to the environmental pathogenesis of fILD. Methods: A retrospective two-cohort study applied satellite-derived PM_2.5 and constituent exposure matching to the residential location of patients with fILD. Robust linear regressions were used to evaluate cohort-specific, epigenome-wide differential blood DNA methylation with increasing pollutant exposures (Illumina MethylationEPIC BeadChip). Cox and linear regressions were used to evaluate associations of cytosine-phosphate-guanine (CpG) loci with transplant-free survival and lung function. A Wilcoxon test was used to evaluate cartilage-associated protein (CRTAP) levels in fILD and control lungs. Measurements and Main Results: The University of Pittsburgh cohort (n = 306) had 5-year median PM_2.5 exposures of 12.1 μg/m³ compared with 5.1 μg/m³ in the University of British Columbia cohort (n = 170). Higher pollutant exposures in the University of Pittsburgh cohort were associated with lower methylation at cg25354716, annotated to CRTAP, a critical extracellular matrix remodeling enzyme. Higher exposures in the University of British Columbia 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 of 0.81 for death or lung transplantation in the meta-analyzed cohorts (95% confidence interval = 0.69-0.96; P = 0.01), whereas the same change in cg01019301 was associated with a hazard ratio of 1.36 (95% confidence interval = 1.07-1.74; P = 0.01). CRTAP protein was more abundant in lungs from patients with fILD compared with those from donor controls (P < 0.001). Conclusions: PM_2.5 is associated with altered blood DNA methylation in fILD. This work identifies novel pollution-sensitive targets that hold potential for therapeutic modulation in fILD.