Sun Jing, Zhao Jianhui, Zhou Siyun, Li Xinxuan, Li Tengfei, Wang Lijuan, Yuan Shuai, Chen Dong, Law Philip J, Larsson Susanna C, Farrington Susan M, Houlston Richard S, Dunlop Malcolm G, Theodoratou Evropi, Li Xue
Department of Big Data in Health Science School of Public Health, and Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK.
J Natl Cancer Inst. 2024 Aug 1;116(8):1303-1312. doi: 10.1093/jnci/djae089.
We aimed to identify plasma and urinary metabolites related to colorectal cancer (CRC) risk and elucidate their mediator role in the associations between modifiable risk factors and CRC.
Metabolite quantitative trait loci were derived from 2 published metabolomics genome-wide association studies, and summary-level data were extracted for 651 plasma metabolites and 208 urinary metabolites. Genetic associations with CRC were obtained from a large-scale genome-wide association study meta-analysis (100 204 cases, 154 587 controls) and the FinnGen cohort (4957 cases, 304 197 controls). Mendelian randomization and colocalization analyses were performed to evaluate the causal roles of metabolites in CRC. Druggability evaluation was employed to prioritize potential therapeutic targets. Multivariable Mendelian randomization and mediation estimation were conducted to elucidate the mediating effects of metabolites on the associations between modifiable risk factors and CRC.
The study identified 30 plasma metabolites and 4 urinary metabolites for CRC. Plasma sphingomyelin and urinary lactose, which were positively associated with CRC risk, could be modulated by drug interventions (ie, olipudase alfa, tilactase). Thirteen modifiable risk factors were associated with 9 metabolites, and 8 of these modifiable risk factors were associated with CRC risk. These 9 metabolites mediated the effect of modifiable risk factors (Actinobacteria, body mass index, waist to hip ratio, fasting insulin, smoking initiation) on CRC.
This study identified key metabolite biomarkers associated with CRC and elucidated their mediator roles in the associations between modifiable risk factors and CRC. These findings provide new insights into the etiology and potential therapeutic targets for CRC and the etiological pathways of modifiable environmental factors with CRC.
我们旨在识别与结直肠癌（CRC）风险相关的血浆和尿液代谢物，并阐明它们在可改变风险因素与CRC之间关联中的中介作用。
代谢物数量性状位点来自2项已发表的代谢组学全基因组关联研究，并提取了651种血浆代谢物和208种尿液代谢物的汇总水平数据。与CRC的遗传关联来自大规模全基因组关联研究荟萃分析（100204例病例，154587例对照）和芬兰基因组队列（4957例病例，304197例对照）。进行孟德尔随机化和共定位分析以评估代谢物在CRC中的因果作用。采用可成药评估对潜在治疗靶点进行优先排序。进行多变量孟德尔随机化和中介估计以阐明代谢物对可改变风险因素与CRC之间关联的中介作用。
该研究确定了30种与CRC相关的血浆代谢物和4种尿液代谢物。与CRC风险呈正相关的血浆鞘磷脂和尿液乳糖可通过药物干预（即olipudase alfa、tilactase）进行调节。13种可改变风险因素与9种代谢物相关，其中8种可改变风险因素与CRC风险相关。这9种代谢物介导了可改变风险因素（放线菌、体重指数、腰臀比、空腹胰岛素、开始吸烟）对CRC的影响。
本研究确定了与CRC相关的关键代谢物生物标志物，并阐明了它们在可改变风险因素与CRC之间关联中的中介作用。这些发现为CRC的病因和潜在治疗靶点以及可改变环境因素与CRC的病因途径提供了新的见解。
