Exposure to air pollution increases susceptibility to ulcerative colitis through epigenetic alterations in CXCR2 and MHC class III regionResearch in context
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
Affiliations
Jie Chen
The Second Affiliated Hospital and School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China
Han Zhang
The Second Affiliated Hospital and School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
Tian Fu
The Second Affiliated Hospital and School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China; Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Westlake University Medical College, Hangzhou, China
Jianhui Zhao
The Second Affiliated Hospital and School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
Jan Krzysztof Nowak
Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, 60572, Poznan, Poland
Rahul Kalla
Medical Research Council Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
Judith Wellens
KU Leuven Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium; Translational Gastro-Intestinal Unit, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK
Shuai Yuan
Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
Alexandra Noble
Translational Gastro-Intestinal Unit, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK
Nicholas T. Ventham
Medical Research Council Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
Malcolm G. Dunlop
Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
Jonas Halfvarson
Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
Ren Mao
Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
Evropi Theodoratou
Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK; Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom; Corresponding author. Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
Jack Satsangi
Translational Gastro-Intestinal Unit, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK; Corresponding author.
Xue Li
The Second Affiliated Hospital and School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Corresponding author.
Summary: 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).
