Background 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. Methods Metabolite quantitative trait loci were derived from two published metabolomics genome-wide association studies (GWASs), and summary-level data were extracted for 651 plasma metabolites and 208 urinary metabolites. Genetic associations with CRC were obtained from a large-scale GWAS meta-analysis (100,204 cases; 154,587 controls) and the FinnGen cohort (4,957 cases; 304,197 controls). Mendelian randomization (MR) and colocalization analyses were performed to evaluate the causal roles of metabolites in CRC. Druggability evaluation was employed to prioritize potential therapeutic targets. Multivariable MR and mediation estimation were conducted to elucidate the mediating effects of metabolites on the associations between modifiable risk factors and CRC. Results The study identified 30 plasma metabolites and four 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 nine metabolites and eight of these modifiable risk factors were associated with CRC risk. These nine metabolites mediated the effect of modifiable risk factors (Actinobacteria, BMI, waist-hip ratio, fasting insulin, smoking initiation) on CRC. Conclusion 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.

中文翻译：

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对基因决定的血浆和尿液代谢物进行系统研究，以发现结直肠癌的潜在干预靶点

背景我们的目的是识别与结直肠癌 (CRC) 风险相关的血浆和尿液代谢物，并阐明它们在可改变的危险因素与 CRC 之间的关联中的中介作用。方法 代谢物数量性状位点源自两项已发表的代谢组学全基因组关联研究 (GWAS)，并提取了 651 种血浆代谢物和 208 种尿液代谢物的汇总数据。与 CRC 的遗传关联来自大规模 GWAS 荟萃分析（100,204 例病例；154,587 名对照）和 FinnGen 队列（4,957 例；304,197 名对照）。进行孟德尔随机化 (MR) 和共定位分析来评估代谢物在 CRC 中的因果作用。采用成药性评估​​来优先考虑潜在的治疗靶点。进行多变量 MR 和中介估计，以阐明代谢物对可改变危险因素与 CRC 之间关联的中介作用。结果 该研究鉴定出 30 种血浆代谢物和 4 种尿液代谢物与 CRC 相关。血浆鞘磷脂和尿乳糖与CRC风险呈正相关，可以通过药物干预（即Olipudase alfa、Tilacase）进行调节。十三个可改变的风险因素与九种代谢物相关，其中八个可改变的风险因素与结直肠癌风险相关。这九种代谢物介导了可改变的危险因素（放线菌、体重指数、腰臀比、空腹胰岛素、吸烟开始）对结直肠癌的影响。结论 本研究确定了与 CRC 相关的关键代谢生物标志物，并阐明了它们在可改变危险因素与 CRC 之间的关联中的调节作用。这些发现为 CRC 的病因学和潜在治疗靶点以及可改变的环境因素与 CRC 的病因学途径提供了新的见解。