Impact of ambient air pollution on colorectal cancer risk and survival: insights from a prospective cohort and epigenetic Mendelian randomization study

孟德尔随机化 结直肠癌 前瞻性队列研究 表观遗传学 医学 DNA甲基化 生命银行 癌症 肿瘤科 队列 队列研究 内科学 生物信息学 生物 遗传学 基因 遗传变异 基因型 基因表达
作者
Fangyuan Jiang,Jianhui Zhao,Jing Sun,Wenxi Chen,Yuyuan Zhao,Siyun Zhou,Shuai Yuan,Maria Timofeeva,Philip Law,Susanna C. Larsson,Dong Chen,Richard S. Houlston,Malcolm G. Dunlop,Evropi Τheodoratou,Xue Li
出处
期刊:EBioMedicine [Elsevier BV]
卷期号:103: 105126-105126 被引量:25
标识
DOI:10.1016/j.ebiom.2024.105126
摘要

BackgroundThis study investigates the associations between air pollution and colorectal cancer (CRC) risk and survival from an epigenomic perspective.MethodsUsing a newly developed Air Pollutants Exposure Score (APES), we utilized a prospective cohort study (UK Biobank) to investigate the associations of individual and combined air pollution exposures with CRC incidence and survival, followed by an up-to-date systematic review with meta-analysis to verify the associations. In epigenetic two-sample Mendelian randomization analyses, we examine the associations between genetically predicted DNA methylation related to air pollution and CRC risk. Further genetic colocalization and gene–environment interaction analyses provided different insights to disentangle pathogenic effects of air pollution via epigenetic modification.FindingsDuring a median 12.97-year follow-up, 5767 incident CRC cases among 428,632 participants free of baseline CRC and 533 deaths in 2401 patients with CRC were documented in the UK Biobank. A higher APES score was associated with an increased CRC risk (HR, 1.03, 95% CI = 1.01–1.06; P = 0.016) and poorer survival (HR, 1.13, 95% CI = 1.03–1.23; P = 0.010), particularly among participants with insufficient physical activity and ever smokers (Pinteraction > 0.05). A subsequent meta-analysis of seven observational studies, including UK Biobank data, corroborated the association between PM2.5 exposure (per 10 μg/m3 increment) and elevated CRC risk (RR,1.42, 95% CI = 1.12–1.79; P = 0.004; I2 = 90.8%). Genetically predicted methylation at PM2.5-related CpG site cg13835894 near TMBIM1/PNKD and cg16235962 near CXCR5, and NO2-related cg16947394 near TMEM110 were associated with an increased CRC risk. Gene-environment interaction analysis confirmed the epigenetic modification of aforementioned CpG sites with CRC risk and survival.InterpretationOur study suggests the association between air pollution and CRC incidence and survival, underscoring the possible modifying roles of epigenomic factors. Methylation may partly mediate pathogenic effects of air pollution on CRC, with annotation to epigenetic alterations in protein-coding genes TMBIM1/PNKD, CXCR5 and TMEM110.FundingXue Li is supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001), the National Nature Science Foundation of China (No. 82204019) and Healthy Zhejiang One Million People Cohort (K-20230085). ET is supported by a Cancer Research UK Career Development Fellowship (C31250/A22804). MGD is supported by the MRC Human Genetics Unit Centre Grant (U127527198).
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