Genetic evidence of circulating metabolites linking to gastric cancers: a two-sample Mendelian randomization study

Observational studies have implicated that blood metabolites were correlated with gastric cancer. This study was designed to reveal the potential causal link between gastric cancer and the levels of circulating metabolites. Single-nucleotide polymorphisms associated with lipid traits in univariate analysis were obtained from the Genome Wide Association Study (GWAS) repositories, involving 8299 European individuals, respectively. Blood metabolites in multivariate analysis were obtained from the latest GWAS Catalog, covering 850 known and 241 unknown metabolites, plus 309 metabolite ratios. Data on gastric cancer were obtained from the FinnGen Consortium, including 279 444 individuals of European descent, 1037 cases of which were gastric cancer. Subsequently, MR analysis was performed using conventional methods, including inverse variance-weighted, weighted median, weighted-mode, simple-mode and MREgger regression to demonstrate the causal relationship between circulating metabolites and gastric cancer. Two-sample Mendelian randomization method showed that seven circulating metabolites (X-24588, SAH to ribothymidine ratio, histidine to asparagine ratio, 1-dihomo-linolenylglycerol, ribothymidine, 2-linoleoylglycerol levels, and 2ʹ-o-methyluridine) were causally associated with the risk of gastric cancer. After verification of MR results and meta-analysis, levels of histidine to asparagine ratio, SAH to ribothymidine ratio, and 2ʹ-o-methyluridine consistently achieved statistical significance. Furthermore, histidine metabolism was identified as the most significant metabolic pathway. It is indicated that three circulating metabolites (histidine to asparagine ratio, SAH to ribothymidine ratio, and 2ʹ-o-methyluridine) achieved statistical significance in the casual relationship with the occurrence of gastric cancer, indicating that histidine metabolism may serve as the crucial metabolic pathway and therapeutic targets for gastric cancer.