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PubMed · 40540633

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

Gillian C Goobie·Najmeh Assadinia·Chen Xi Yang·Fanny Chu·Rachel L Clifford·Joel D Cooper·James P Fabisiak·Kevin F Gibson·Kerri A Johannson·Daniel J Kass·Sharon E Kim·Xiaoyun Li·Kathleen O Lindell·Daniel-Costin Marinescu·Dragos M Vasilescu·Victoria Wang·Christopher Carlsten·S Mehdi Nouraie·Christopher J Ryerson·Tillie L Hackett·Yingze Zhang
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Abstract

Rationale: Particulate matter &#x2a7d;2.5 &#x3bc;m (PM2.5) adversely impacts patients with fibrotic interstitial lung disease (fILD). Objectives: We sought to determine whether PM2.5-associated epigenetic alterations contribute to the environmental pathogenesis of fILD. Methods: A retrospective two-cohort study applied satellite-derived PM2.5 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&#x2009;=&#x2009;306) had 5-year median PM2.5 exposures of 12.1 &#x3bc;g/m3 compared with 5.1 &#x3bc;g/m3 in the University of British Columbia cohort (n&#x2009;=&#x2009;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&#x2009;=&#x2009;0.69-0.96; P&#x2009;=&#x2009;0.01), whereas the same change in cg01019301 was associated with a hazard ratio of 1.36 (95% confidence interval&#x2009;= 1.07-1.74; P&#x2009;=&#x2009;0.01). CRTAP protein was more abundant in lungs from patients with fILD compared with those from donor controls (P&#x2009;<&#x2009;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.

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HumansMaleFemaleParticulate MatterMiddle AgedLung Diseases, InterstitialRetrospective StudiesDNA MethylationAgedEpigenomeEnvironmental ExposureEpigenesis, GeneticAir PollutionAir PollutantsCohort StudiesDNA methylationair pollutionepigeneticsinterstitial lung diseaseparticulate matterJournal ArticleResearch Support, Non-U.S. Gov't

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Gillian C Goobie, Najmeh Assadinia, Chen Xi Yang, Fanny Chu, Rachel L Clifford, Joel D Cooper, James P Fabisiak, Kevin F Gibson, Kerri A Johannson, Daniel J Kass, Sharon E Kim, Xiaoyun Li, Kathleen O Lindell, Daniel-Costin Marinescu, Dragos M Vasilescu, Victoria Wang, Christopher Carlsten, S Mehdi Nouraie, Christopher J Ryerson, Tillie L Hackett, Yingze Zhang. 2025. Epigenome-Wide Analysis Identifies Pollution-Sensitive Loci in Fibrotic Interstitial Lung Disease.. https://doi.org/10.1164/rccm.202407-1504oc

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