Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Dec:110:105443.
doi: 10.1016/j.ebiom.2024.105443. Epub 2024 Nov 13.

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

Jie Chen  1 , Han Zhang  2 , Tian Fu  3 , Jianhui Zhao  2 , Jan Krzysztof Nowak  4 , Rahul Kalla  5 , Judith Wellens  6 , Shuai Yuan  7 , Alexandra Noble  8 , Nicholas T Ventham  5 , Malcolm G Dunlop  9 , Jonas Halfvarson  10 , Ren Mao  11 , Evropi Theodoratou  12 , Jack Satsangi  13 , Xue Li  14
Affiliations

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

Jie Chen et al. EBioMedicine. 2024 Dec.

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 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).

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

PubMed Disclaimer

Conflict of interest statement

Declaration of interests JKN reports consulting for Procter & Gamble and grant support from the Biocodex Microbiota Foundation, outside of the submitted work. All the remaining authors declare no potential or actual conflict of interest to the work presented in this paper.

Figures

Fig. 1
Fig. 1
Flow chart of the study. IBD, inflammatory bowel disease; CD, Crohn's disease; UC, ulcerative colitis; PM, particulate matter; NOx, nitrogen oxides; NO2, nitrogen dioxide; EWAS, Epigenome-wide association studies; GWAS, genome-wide association study; MR, Mendelian randomization; mQTL, methylation quantitative trait loci; DNA, deoxyribonucleic acid; MHC, major histocompatibility complex; CXCR2, CXC motif chemokine receptor 2.
Fig. 2
Fig. 2
The effect of gene regulated by PM2.5-related DNA methylation on the risk of ulcerative colitis. The blue line means P = 0.05, and the red line means the threshold of FDR correction.
Fig. 3
Fig. 3
The effect of gene regulated by NO2-related DNA methylation on the risk of ulcerative colitis. The blue line means P = 0.05, and the red line means the threshold of FDR correction.
Fig. 4
Fig. 4
Regional plot of colocalization evidence of CpG site methylation and ulcerative colitis susceptibility. Panel A displays the P-value of the SNP and mQTL in corresponding GWAS and EWAS. In the Panel B and C, the horizontal axis demonstrates the base position of the SNP and mQTL, and the vertical axis is the P-value of the SNP and mQTL, respectively.
See this image and copyright information in PMC

References

    1. Ng S.C., Shi H.Y., Hamidi N., et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2017;390(10114):2769–2778. - PubMed
    1. Kuenzig M.E., Fung S.G., Marderfeld L., et al. Twenty-first century trends in the global epidemiology of pediatric-onset inflammatory bowel disease: systematic review. Gastroenterology. 2022;162(4):1147–1159.e4. - PubMed
    1. Jones G.R., Lyons M., Plevris N., et al. IBD prevalence in Lothian, Scotland, derived by capture-recapture methodology. Gut. 2019;68(11):1953–1960. - PMC - PubMed
    1. Liu Z., Liu R., Gao H., et al. Genetic architecture of the inflammatory bowel diseases across East Asian and European ancestries. Nat Genet. 2023;55(5):796–806. - PMC - PubMed
    1. Ordás I., Eckmann L., Talamini M., Baumgart D.C., Sandborn W.J. Ulcerative colitis. Lancet. 2012;380(9853):1606–1619. - PubMed