Abstract Background This study aims to comprehensively evaluate the association between early life exposure to smoking and the risk of inflammatory bowel disease (IBD), and to explore the role of DNA methylation in the effect of maternal smoking during pregnancy (MSDP) on IBD risk of offspring and whether common epigenetic pathways exist across different life stages. Methods We first conducted a prospective cohort study and meta-analysis to evaluate the association between smoking exposure from prenatal to adolescence periods and the IBD risk across lifespan stages. Leveraging available genome-wide association (GWAS, n = 59,957) and epigenome-wide association studies (EWAS, n = 161∼6,685), an epigenetic Mendelian randomization (MR) study was then conducted to characterize dynamic DNA methylation signatures associated with early-life smoke exposure and their effect on IBD pathogenesis. External EWAS of IBD, colocalization analysis, and gene expression and single cell sequencing analyses in colorectal tissues were interrogated to validate epigenetic signals. Finally, we explored common DNA methylation pathways involved in the effects of smoking exposure on IBD across different life stages. Results With a median follow-up of 13·9 years, the observational study in UK Biobank cohort demonstrated that MSDP was associated with increased risk of IBD (HR = 1·13, 95%CI: 1·05-1·22), CD (HR = 1·21, 95%CI: 1·05-1·39), and UC (HR = 1·11, 95%CI: 1·01-1·23) in offspring. Individuals who started smoking in adolescence had a higher risk of developing CD (HR = 1·79, 95%CI: 1·44-2·23) and IBD (HR = 1·35, 95%CI: 1·18-1·54). Meta-analysis of seven cohort studies further verified MSDP to be significantly associated with the risk of IBD (RR = 1·42, 95%CI: 1·19-1·70), CD (RR = 1·12, 95%CI: 1·02-1·22), and UC (RR = 1·08, 95%CI: 1·01-1·16) in offspring. MSDP-associated DNA methylation alterations in ADCY7 (newborn), AKAP8L (newborn), TIGD7 (newborn), and TNF/LTA (within HLA Class III region, across newborn and adult) were significantly correlated with increased risk of CD in offspring; MSDP-induced DNA methylation changes in PRRT1 or use HLA CLASS III (newborn), AHRR (across life stages), and MYO1G (across life stages) showed significant associations with UC risk in offspring. The alterations of DNA methylation status within AHRR, MYO1G, and HLA loci associated with smoking exposure were present throughout early life. Conclusion We hereby confirm that maternal smoking during pregnancy acts as an independent risk factor for both CD and UC in offspring. Our study further indicates that the impact of passive exposure to maternal smoking encompasses epigenetic modifications within the HLA Class III Region, AHRR, and MYO1G at multiple developmental stages. Conflict of interest: Zhang, Han: No conflict of interest Zhao, Jianhui: I acknowledge support from the Key Laboratory of Integrated Care for Geriatric Chronic Diseases (Kunming Medical University, School of Nursing), Yunnan Provincial Education Department (Grant No. 2024HTHLYB05), and from the Fundamental Research Funds for the Central Universities (No. 2024BSSXM20). I declare no other conflicts of interest. Chen, Jie: None to Declare Ma, Xinyi: No conflict of interest Zhou, Siyun: No conflict of interest Noble, Alexandra: No conflict of interest Kalla, Rahul: No conflict of interest Wellens, Judith: No conflicts Liu, Kun: No conflict of interest Theodoratou, Evropi: No conflict of interest Satsangi, Jack: Grant: Grants to Oxford University from Helmsley Trust & European Community. Li, Xue: No conflict of interest
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