Abstract
BACKGROUND: Gastric cancer (GC) remains one of the predominant malignant tumors within the digestive tract, yet its underlying biological mechanisms remain elusive. The primary objective of this study is to delineate the causal relationship between circulating metabolites and GC. METHOD: The primary Mendelian randomization (MR) analysis was based on three large GWAS datasets. While the inverse variance weighted served as the primary analysis technique for investigating causal relationships, additional sensitivity analyses were facilitated through methods such as MR-PRESSO, the weighted median, and MR-Egger. Subsequently, replication, meta-analysis, and multivariable MR were executed using another GC GWAS. RESULTS: The results of this study indicated significant associations between three metabolites 3-methyl-2-oxovalerate (OR 5.8, 95%CI: 1.53-22.05, p = 0.0099), piperine (OR 2.05, 95%CI: 1.13-3.7, p = 0.0175), Phe-Phe dipeptide (OR 0.16, 95%CI: 0.03-0.93, p = 0.0409) and GC. CONCLUSION: The present study provides evidence supporting a causal relationship between these three circulating metabolites and GC risk. Elevated levels of 3-methyl-2-oxovalerate and piperine may increase the risk of GC, while Phe-Phe dipeptide may have a protective effect. By integrating genomics and metabolomics, we offer a novel perspective on the biological mechanisms underlying GC. Such insights have the potential to enhance strategies for the screening, prevention, and treatment of GC.