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

IF 19.4 1区医学 Q1 CRITICAL CARE MEDICINE

American journal of respiratory and critical care medicine Pub Date : 2025-06-20 DOI:10.1164/rccm.202407-1504oc

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 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

{"title":"Epigenome-Wide Analysis Identifies Pollution-Sensitive Loci in Fibrotic Interstitial Lung Disease.","authors":"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 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","doi":"10.1164/rccm.202407-1504oc","DOIUrl":null,"url":null,"abstract":"RATIONALE\r\nParticulate matter <=2.5um (PM2.5) adversely impacts patients with fibrotic interstitial lung disease (fILD).\r\n\r\nOBJECTIVE\r\nTo determine whether PM2.5-associated epigenetic alterations contribute to the environmental pathogenesis of fILD.\r\n\r\nMETHODS\r\nRetrospective two-cohort study applying satellite-derived PM2.5 and constituent exposure matching to the residential location of patients with fILD. Robust linear regressions evaluated cohort-specific epigenome-wide differential blood DNA methylation with increasing pollutant exposures (Illumina MethylationEPIC BeadChip). Cox and linear regressions evaluated associations of cytosine-phosphate-guanine (CpG) loci with transplant-free survival and lung function. Wilcoxon test evaluated cartilage-associated protein (CRTAP) levels in fILD and control lungs.\r\n\r\nRESULTS\r\nThe University of Pittsburgh (UPitt) cohort (n=306) had 5-year median PM2.5 exposures of 12.1ug/m3 compared with 5.1ug/m3 in the University of British Columbia (UBC) cohort (n=170). Higher pollutant exposures in the UPitt cohort were associated with lower methylation at cg25354716, annotated to CRTAP, a critical extracellular matrix remodeling enzyme. Higher exposures in the UBC 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 (HR) of 0.81 for death or lung transplantation in the meta-analyzed cohorts (95%CI 0.69-0.96, p=0.01), whereas the same change in cg01019301 was associated with a HR of 1.36 (95%CI 1.07-1.74, p=0.01). CRTAP protein was more abundant in lungs from patients with fILD compared with donor controls (p<0.001).\r\n\r\nCONCLUSIONS\r\nPM2.5 is associated with altered blood DNA methylation in fILD. This work identifies novel pollution-sensitive targets that hold potential for therapeutic modulation in fILD.","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":"195 1","pages":""},"PeriodicalIF":19.4000,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of respiratory and critical care medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1164/rccm.202407-1504oc","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CRITICAL CARE MEDICINE","Score":null,"Total":0}

引用次数: 0

Abstract

RATIONALE Particulate matter <=2.5um (PM2.5) adversely impacts patients with fibrotic interstitial lung disease (fILD). OBJECTIVE To determine whether PM2.5-associated epigenetic alterations contribute to the environmental pathogenesis of fILD. METHODS Retrospective two-cohort study applying satellite-derived PM2.5 and constituent exposure matching to the residential location of patients with fILD. Robust linear regressions evaluated cohort-specific epigenome-wide differential blood DNA methylation with increasing pollutant exposures (Illumina MethylationEPIC BeadChip). Cox and linear regressions evaluated associations of cytosine-phosphate-guanine (CpG) loci with transplant-free survival and lung function. Wilcoxon test evaluated cartilage-associated protein (CRTAP) levels in fILD and control lungs. RESULTS The University of Pittsburgh (UPitt) cohort (n=306) had 5-year median PM2.5 exposures of 12.1ug/m3 compared with 5.1ug/m3 in the University of British Columbia (UBC) cohort (n=170). Higher pollutant exposures in the UPitt cohort were associated with lower methylation at cg25354716, annotated to CRTAP, a critical extracellular matrix remodeling enzyme. Higher exposures in the UBC 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 (HR) of 0.81 for death or lung transplantation in the meta-analyzed cohorts (95%CI 0.69-0.96, p=0.01), whereas the same change in cg01019301 was associated with a HR of 1.36 (95%CI 1.07-1.74, p=0.01). CRTAP protein was more abundant in lungs from patients with fILD compared with donor controls (p<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.

查看原文本刊更多论文

全表观基因组分析确定了纤维化间质性肺病的污染敏感位点。

<=2.5um的颗粒物（PM2.5）对纤维化间质性肺疾病（field）患者有不利影响。目的探讨pm2.5相关表观遗传改变是否与field的环境发病机制有关。方法回顾性双队列研究，应用卫星获取的PM2.5和成分暴露与field患者居住地匹配。鲁棒线性回归评估随污染物暴露增加的群体特异性表观基因组范围的血液DNA甲基化差异（Illumina MethylationEPIC BeadChip）。Cox和线性回归评估了胞嘧啶-磷酸-鸟嘌呤（CpG）位点与无移植生存和肺功能的关系。Wilcoxon试验评估了field和对照肺中软骨相关蛋白（CRTAP）的水平。结果匹兹堡大学（UPitt）队列（n=306）的5年PM2.5暴露中位数为12.1ug/m3，而不列颠哥伦比亚大学（UBC）队列（n=170）的5年PM2.5暴露中位数为5.1ug/m3。UPitt队列中较高的污染物暴露与较低的cg25354716甲基化相关，注释为CRTAP，一种关键的细胞外基质重塑酶。UBC队列中较高的暴露与cg01019301较高的甲基化相关，注释为TLN2 (talin-2)，一种参与成纤维细胞迁移的细胞骨架蛋白。在荟萃分析队列中，cg25354716甲基化增加10%与死亡或肺移植的风险比（HR）为0.81相关（95%CI 0.69-0.96, p=0.01），而cg01019301甲基化增加10%与风险比（HR）为1.36相关（95%CI 1.07-1.74, p=0.01）。与供体对照组相比，肺组织中CRTAP蛋白含量更高（p<0.001）。结论spm2.5与肺组织中血液DNA甲基化改变有关。这项工作确定了新的污染敏感靶点，在field中具有治疗调节的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

American journal of respiratory and critical care medicine 医学-呼吸系统

CiteScore

27.30

自引率

4.50%

发文量

1313

审稿时长

3-6 weeks

期刊介绍： The American Journal of Respiratory and Critical Care Medicine focuses on human biology and disease, as well as animal studies that contribute to the understanding of pathophysiology and treatment of diseases that affect the respiratory system and critically ill patients. Papers that are solely or predominantly based in cell and molecular biology are published in the companion journal, the American Journal of Respiratory Cell and Molecular Biology. The Journal also seeks to publish clinical trials and outstanding review articles on areas of interest in several forms. The State-of-the-Art review is a treatise usually covering a broad field that brings bench research to the bedside. Shorter reviews are published as Critical Care Perspectives or Pulmonary Perspectives. These are generally focused on a more limited area and advance a concerted opinion about care for a specific process. Concise Clinical Reviews provide an evidence-based synthesis of the literature pertaining to topics of fundamental importance to the practice of pulmonary, critical care, and sleep medicine. Images providing advances or unusual contributions to the field are published as Images in Pulmonary, Critical Care, Sleep Medicine and the Sciences. A recent trend and future direction of the Journal has been to include debates of a topical nature on issues of importance in pulmonary and critical care medicine and to the membership of the American Thoracic Society. Other recent changes have included encompassing works from the field of critical care medicine and the extension of the editorial governing of journal policy to colleagues outside of the United States of America. The focus and direction of the Journal is to establish an international forum for state-of-the-art respiratory and critical care medicine.