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

Abstract

<b>Rationale:</b> Particulate matter ⩽2.5 μm (PM_2.5) adversely impacts patients with fibrotic interstitial lung disease (fILD). <b>Objectives:</b> We sought to determine whether PM_2.5-associated epigenetic alterations contribute to the environmental pathogenesis of fILD. <b>Methods:</b> 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. <b>Measurements and Main Results:</b> The University of Pittsburgh cohort (<i>n</i> = 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 (<i>n</i> = 170). Higher pollutant exposures in the University of Pittsburgh cohort were associated with lower methylation at cg25354716, annotated to <i>CRTAP</i>, a critical extracellular matrix remodeling enzyme. Higher exposures in the University of British Columbia cohort were associated with higher methylation at cg01019301, annotated to <i>TLN2</i> (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; <i>P</i> = 0.01), whereas the same change in cg01019301 was associated with a hazard ratio of 1.36 (95% confidence interval = 1.07-1.74; <i>P</i> = 0.01). CRTAP protein was more abundant in lungs from patients with fILD compared with those from donor controls (<i>P</i> < 0.001). <b>Conclusions:</b> 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.