Jie Chen, Han Zhang, Tian Fu, Jianhui Zhao, Jan Krzysztof Nowak, Rahul Kalla, Judith Wellens, Shuai Yuan, Alexandra Noble, Nicholas T Ventham, Malcolm G Dunlop, Jonas Halfvarson, Ren Mao, Evropi Theodoratou, Jack Satsangi, Xue Li
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引用次数: 0
摘要
背景：本研究旨在证实空气污染与溃疡性结肠炎（UC）和克罗恩病（CD）之间的关系，探讨空气污染与遗传学和生活方式之间的相互作用，并描述潜在的表观遗传学机制：我们从英国生物库中识别了超过 45 万人，并调查了空气污染与炎症性肠病（IBD）发病之间的关系。我们利用 Cox 回归计算危险比 (HR)，同时还探讨了与遗传和生活方式因素的潜在相互作用。此外，我们还进行了表观遗传孟德尔随机化（MR）分析，以研究空气污染相关 DNA 甲基化与 UC 之间的关联。最后，通过对 UC 进行全基因组 DNA 甲基化分析以及共定位和基因表达分析，验证了我们的研究结果：结果：较高的氮氧化物（HR = 1.20，95% CI = 1.05-1.38）、二氧化氮（HR = 1.19，95% CI = 1.03-1.36）、PM2.5（HR = 1.19，95% CI = 1.05-1.36）暴露和综合空气污染评分（HR = 1.26，95% CI = 1.11-1.45）与UC事件相关，但与CD无关。遗传风险评分和生活方式之间存在相互作用。在MR分析中，我们发现与PM2.5和二氧化氮暴露相关的5个和22个甲基化CpG位点与UC显著相关。在全基因组DNA甲基化分析、共定位分析和结肠组织分析中，验证了CXCR2和MHC III类区域内位点的DNA甲基化改变：我们报告了空气污染与 UC 之间的潜在因果关系，这种关系受到生活方式和遗传因素的影响。所涉及的生物学途径包括关键遗传位点的表观遗传学改变，包括 CXCR2 和 MHC III 类区域内的易感位点：薛莉获得浙江省杰出青年学者自然科学基金（LR22H260001）和国家自然科学基金（编号：82204019）的资助。ET得到了英国皇家研究理事会职业发展奖学金（C31250/A22804）和佛兰德斯研究基金会（FWO）的资助。JW获得比利时博士奖学金战略基础研究（SB）基金（1S06023N）的资助。JKN得到了波兰国家科学中心的资助（编号：2020/39/D/NZ5/02720）。IBD Character得到了欧盟第七框架计划[FP7]赠款IBD Character（编号：2858546）的支持。
Exposure to air pollution increases susceptibility to ulcerative colitis through epigenetic alterations in CXCR2 and MHC class III region.
Background: This study aims to confirm the associations of air pollution with ulcerative colitis (UC) and Crohn's disease (CD); to explore interactions with genetics and lifestyle; and to characterize potential epigenetic mechanisms.
Methods: We identified over 450,000 individuals from the UK Biobank and investigated the relationship between air pollution and incident inflammatory bowel disease (IBD). Cox regression was utilized to calculate hazard ratios (HRs), while also exploring potential interactions with genetics and lifestyle factors. Additionally, we conducted epigenetic Mendelian randomization (MR) analyses to examine the association between air pollution-related DNA methylation and UC. Finally, our findings were validated through genome-wide DNA methylation analysis of UC, as well as co-localization and gene expression analyses.
Findings: Higher exposures to NOx (HR = 1.20, 95% CI 1.05-1.38), NO2 (HR = 1.19, 95% CI = 1.03-1.36), PM2.5 (HR = 1.19, 95% CI = 1.05-1.36) and combined air pollution score (HR = 1.26, 95% CI = 1.11-1.45) were associated with incident UC but not CD. Interactions with genetic risk score and lifestyle were observed. In MR analysis, we found five and 22 methylated CpG sites related to PM2.5 and NO2 exposure to be significantly associated with UC. DNA methylation alterations at CXCR2 and sites within the MHC class III region, were validated in genome-wide DNA methylation analysis, co-localization analysis and analysis of colonic tissue.
Interpretation: We report a potential causal association between air pollution and UC, modified by lifestyle and genetic influences. Biological pathways implicated include epigenetic alterations in key genetic loci, including CXCR2 and susceptible loci within MHC class III region.
Funding: Xue Li was supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001) and the National Nature Science Foundation of China (No. 82204019). ET was supported by the CRUK Career Development Fellowship (C31250/A22804) and the Research Foundation Flanders (FWO). JW was supported by Belgium by a PhD Fellowship strategic basic research (SB) grant (1S06023N). JKN was supported by the National Science Center, Poland (No. 2020/39/D/NZ5/02720). The IBD Character was supported by the European Union's Seventh Framework Programme [FP7] grant IBD Character (No. 2858546).
EBioMedicineBiochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
17.70
自引率
0.90%
发文量
579
审稿时长
5 weeks
期刊介绍：
eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.
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