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

Area of Science:

• Environmental Epigenetics
• Pulmonary Medicine
• Toxicology

Background:

• Particulate matter ≤2.5µm (PM_2.5) exacerbates fibrotic interstitial lung disease (fILD).
• Epigenetic modifications are implicated in environmental disease pathogenesis.
• Understanding PM_2.5's role in fILD requires investigating its impact on DNA methylation.

Purpose of the Study:

• To investigate the association between PM_2.5 exposure and epigenetic alterations in patients with fILD.
• To identify specific DNA methylation changes (CpG loci) related to PM_2.5 exposure.
• To evaluate the correlation between these epigenetic changes and clinical outcomes, including survival and lung function.

Main Methods:

• A retrospective study of two fILD patient cohorts (University of Pittsburgh and University of British Columbia).
• Satellite-derived PM_2.5 exposure data matched to patient residential locations.
• Epigenome-wide DNA methylation analysis using Illumina MethylationEPIC BeadChip and robust linear regressions.
• Cox and linear regressions to assess associations between CpG loci methylation, transplant-free survival, and lung function.
• Wilcoxon test to compare cartilage-associated protein (CRTAP) levels in fILD and control lung tissues.

Main Results:

• Higher PM_2.5 exposure in the UPitt cohort correlated with decreased methylation at cg25354716 (CRTAP gene).
• Higher PM_2.5 exposure in the UBC cohort correlated with increased methylation at cg01019301 (TLN2 gene).
• Increased methylation in cg25354716 was associated with improved survival (HR 0.81), while increased cg01019301 methylation was linked to worse survival (HR 1.36).
• CRTAP protein levels were significantly higher in fILD lungs compared to controls.

Conclusions:

• PM_2.5 exposure is demonstrably associated with altered DNA methylation patterns in blood of fILD patients.
• Identified specific methylation sites (cg25354716 in CRTAP, cg01019301 in TLN2) as potential biomarkers and therapeutic targets.
• These findings highlight novel pollution-sensitive epigenetic targets for potential therapeutic intervention in fILD.