Department of Big Data in Health Science School of Public Health, and Centre of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Centre for Population Health Sciences, Usher Institute, University of Edinburgh, Edinburgh, UK.
Br J Cancer. 2023 Oct;129(8):1306-1313. doi: 10.1038/s41416-023-02397-6. Epub 2023 Aug 22.
Tobacco smoking is suggested as a risk factor for colorectal cancer (CRC), but the complex relationship and the potential pathway are not fully understood.
We performed two-sample Mendelian randomisation (MR) analyses with genetic instruments for smoking behaviours and related DNA methylation in blood and summary-level GWAS data of colorectal cancer to disentangle the relationship. Colocalization analyses and prospective gene-environment interaction analyses were also conducted as replication.
Convincing evidence was identified for the pathogenic effect of smoking initiation on CRC risk and suggestive evidence was observed for the protective effect of smoking cessation in the univariable MR analyses. Multivariable MR analysis revealed that these associations were independent of other smoking phenotypes and alcohol drinking. Genetically predicted methylation at CpG site cg17823346 [ZMIZ1] were identified to decrease CRC risk; while genetically predicted methylation at cg02149899 would increase CRC risk. Colocalization and gene-environment interaction analyses added further evidence to the relationship between epigenetic modification at cg17823346 [ZMIZ1] as well as cg02149899 and CRC risk.
Our study confirms the significant association between tobacco smoking, DNA methylation and CRC risk and yields a novel insight into the pathogenic effect of tobacco smoking on CRC risk.
吸烟被认为是结直肠癌（CRC）的一个风险因素，但这种复杂的关系及其潜在的途径尚未完全了解。
我们使用吸烟行为和血液中相关 DNA 甲基化的遗传工具以及结直肠癌的汇总水平 GWAS 数据进行了两样本 Mendelian 随机化（MR）分析，以理清这种关系。还进行了共定位分析和前瞻性基因-环境相互作用分析作为复制。
在单变量 MR 分析中，有确凿的证据表明吸烟起始与 CRC 风险之间存在致病性关联，有提示性证据表明戒烟对 CRC 风险具有保护作用。多变量 MR 分析表明，这些关联独立于其他吸烟表型和饮酒。鉴定出 CpG 位点 cg17823346[ZMIZ1]上的遗传预测甲基化可降低 CRC 风险；而 cg02149899 上的遗传预测甲基化则会增加 CRC 风险。共定位和基因-环境相互作用分析为 cg17823346[ZMIZ1]和 cg02149899 与 CRC 风险之间的关系提供了进一步的证据。
我们的研究证实了吸烟、DNA 甲基化与 CRC 风险之间的显著关联，并为吸烟对 CRC 风险的致病作用提供了新的见解。
