Accelerated epigenetic ageing worsens survival and mediates environmental stressors in fibrotic interstitial lung disease.

IF 21 1区医学 Q1 RESPIRATORY SYSTEM

European Respiratory Journal Pub Date : 2025-06-05 Print Date: 2025-06-01 DOI:10.1183/13993003.01618-2024

Gillian C Goobie, Daniel-Costin Marinescu, Ayodeji Adegunsoye, Jean Bourbeau, Christopher Carlsten, Rachel L Clifford, Dany Doiron, Qingling Duan, Kevin F Gibson, Amanda Grant-Orser, Ana I Hernandez Cordero, Kerri A Johannson, Daniel J Kass, Sharon E Kim, Janice M Leung, Xiaoyun Li, Wan Tan, Chen Xi Yang, S Mehdi Nouraie, Christopher J Ryerson, Tillie L Hackett, Yingze Zhang

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引用次数: 0

Abstract

Background: The role of epigenetic ageing in the environmental pathogenesis and prognosis of fibrotic interstitial lung disease (fILD) is unclear. We evaluated whether ambient particulate matter with diameter ≤2.5 μm (PM_2.5) and neighbourhood disadvantage exposures are associated with accelerated epigenetic ageing, and whether epigenetic age is associated with adverse clinical outcomes in patients with fILD.

Methods: This multicentre, international, cohort study included patients with fILD from the University of Pittsburgh (UPitt, n=306) and University of British Columbia (UBC, n=170). 5-year PM_2.5 exposures were estimated using satellite-derived hybrid models. Neighbourhood disadvantage was calculated using US and Canadian census-based metrics. Epigenetic age difference (EAD=epigenetic age-chronological age) was calculated using GrimAge analysis of blood DNA methylation data. Linear models assessed associations of exposures with EAD. Cox models assessed associations of EAD with transplant-free survival. Causal mediation analysis evaluated EAD mediation of exposure-survival relationships.

Results: Median epigenetic age was 11.7 years older than chronological age in patients with fILD. In combined cohort analysis, each interquartile range (IQR) increase in PM_2.5 was associated with 2.88 years (95% CI 1.39-4.38; p<0.001) increased EAD. In UPitt, each IQR neighbourhood disadvantage increase was associated with 1.16 years (95% CI 0.22-2.09; p=0.02) increased EAD. Increased EAD was associated with worse transplant-free survival (hazard ratio 1.17 per 1-year increase in EAD, 95% CI 1.10-1.24; p<0.001), with EAD mediating 40% of the PM_2.5-survival relationship and 59% of the neighbourhood disadvantage-survival relationship. Epigenetic age was also more strongly associated with transplant-free survival than chronological age.

Conclusions: Epigenetic age acceleration is associated with worse survival and mediates adverse exposure impacts in fILD.

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在纤维化间质性肺疾病中，加速的表观遗传衰老恶化了生存并介导了环境应激因子。

背景：表观遗传衰老在纤维化间质性肺疾病（field）的环境发病机制和预后中的作用尚不清楚。我们评估了环境颗粒物≤2.5 μm （PM2.5）和邻里不利暴露是否与加速表观遗传衰老有关，以及表观遗传年龄是否与field患者的不良临床结果有关。方法：这项多中心、国际队列研究纳入了来自匹兹堡大学（UPitt, n=306）和不列颠哥伦比亚大学（UBC, n=170）的field患者。使用卫星衍生模型估算了5年PM2.5暴露量。邻里劣势是根据美国和加拿大人口普查的指标来计算的。表观遗传年龄差异（EAD=表观遗传年龄-实足年龄）使用GrimAge分析血液DNA甲基化数据计算。线性模型评估暴露与EAD的关系。Cox模型评估EAD与无移植生存的关系。因果中介分析评估了EAD对暴露-生存关系的中介作用。结果：field患者的中位表观遗传年龄比实足年龄大11.7岁。在联合队列分析中，PM2.5的每四分位数范围（IQR）增加与2.88年相关（95%CI 1.39-4.38, p2.5-生存关系和59%的邻里不利生存关系）。表观遗传年龄与无移植存活的关系也比实足年龄更强。结论：表观遗传年龄加速与较差的生存率相关，并介导field的不良暴露影响。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

European Respiratory Journal 医学-呼吸系统

CiteScore

27.50

自引率

3.30%

发文量

345

审稿时长

2-4 weeks

期刊介绍： The European Respiratory Journal (ERJ) is the flagship journal of the European Respiratory Society. It has a current impact factor of 24.9. The journal covers various aspects of adult and paediatric respiratory medicine, including cell biology, epidemiology, immunology, oncology, pathophysiology, imaging, occupational medicine, intensive care, sleep medicine, and thoracic surgery. In addition to original research material, the ERJ publishes editorial commentaries, reviews, short research letters, and correspondence to the editor. The articles are published continuously and collected into 12 monthly issues in two volumes per year.