Systematic investigation of genetically determined plasma and urinary metabolites to discover potential interventional targets for colorectal cancer

作者：Jing Sun, Jianhui Zhao, Siyun Zhou, Xinxuan Li, Tengfei Li, Lijuan Wang, Shuai Yuan, Dong Chen, Philip Law, Susanna C. Larsson, Susan M. Farrington, Richard S. Houlston, Malcolm G. Dunlop, Evropi Τheodoratou, Xue Li · 发表于：JNCI Journal of the National Cancer Institute · 年份：2024 · DOI：10.1093/jnci/djae089 · 被引用次数：19 · 研究领域：Metabolomics and Mass Spectrometry Studies、Sphingolipid Metabolism and Signaling、Genetic Associations and Epidemiology

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 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. RESULTS: 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 h...