Exposure to air pollution increases susceptibility to ulcerative colitis through epigenetic alterations in CXCR2 and MHC class III region

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

doi:10.1016/j.ebiom.2024.105443

Exposure to air pollution increases susceptibility to ulcerative colitis through epigenetic alterations in CXCR2 and MHC class III region

EBioMedicine. 2024 Nov 12:110:105443. doi: 10.1016/j.ebiom.2024.105443. Online ahead of print.

Authors

Jie Chen¹, Han Zhang², Tian Fu³, Jianhui Zhao², Jan Krzysztof Nowak⁴, Rahul Kalla⁵, Judith Wellens⁶, Shuai Yuan⁷, Alexandra Noble⁸, Nicholas T Ventham⁵, Malcolm G Dunlop⁹, Jonas Halfvarson¹⁰, Ren Mao¹¹, Evropi Theodoratou¹², Jack Satsangi¹³, Xue Li¹⁴

Affiliations

¹ 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.
² The Second Affiliated Hospital and School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
³ 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.
⁴ Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, 60572, Poznan, Poland.
⁵ Medical Research Council Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
⁶ 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.
⁷ Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁸ Translational Gastro-Intestinal Unit, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK.
⁹ Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
¹⁰ Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
¹¹ Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
¹² 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. Electronic address: e.theodoratou@ed.ac.uk.
¹³ Translational Gastro-Intestinal Unit, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK. Electronic address: jack.satsangi@ndm.ox.ac.uk.
¹⁴ The Second Affiliated Hospital and School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. Electronic address: xueli157@zju.edu.cn.

PMID: 39536393
DOI: 10.1016/j.ebiom.2024.105443

Abstract

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 NO_x (HR = 1.20, 95% CI 1.05-1.38), NO₂ (HR = 1.19, 95% CI = 1.03-1.36), PM_2.5 (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 PM_2.5 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).

Keywords: Air pollution; DNA methylation; Inflammatory bowel disease; MHC III region; Mendelian randomization.