Plasma L-aspartic acid predicts the risk of gastric cancer and modifies the primary prevention effect: a multistage metabolomic profiling and Mendelian randomization study

Abstract

Objective: Based on multistage metabolomic profiling and Mendelian randomization analyses, the current study identified plasma metabolites that predicted the risk of developing gastric cancer (GC) and determined whether key metabolite levels modified the GC primary prevention effects. Methods: Plasma metabolites associated with GC risk were identified through a case-control study. Bi-directional two-sample Mendelian randomization analyses were performed to determine potential causal relationships utilizing the Shandong Intervention Trial (SIT), a nested case-control study of the Mass Intervention Trial in Linqu, Shandong province (MITS), China, the UK Biobank, and the FinnGen project. Results: A higher genetic risk score for plasma L-aspartic acid was significantly associated with an increased GC risk in the northern Chinese population (SIT: HR = 1.26 per 1 SD change, 95% CI: 1.07–1.49; MITS: HR = 1.07, 95% CI: 1.00–1.14) and an increased gastric adenocarcinoma risk in FinnGen (OR = 1.68, 95% CI: 1.16–2.45). Genetically predicted plasma L-aspartic acid levels also modified the GC primary prevention effects with the beneficial effect of Helicobacter pylori eradication notably observed among individuals within the top quartile of L-aspartic acid level (P-interaction = 0.098) and the beneficial effect of garlic supplementation only for those within the lowest quartile of L-aspartic acid level ( P-interaction = 0.02). Conclusions: Elevated plasma L-aspartic acid levels significantly increased the risk of developing GC and modified the effects of GC primary prevention. Further studies from other populations are warranted to validate the modification effect of plasma L-aspartic acid levels on GC prevention and to elucidate the underlying mechanisms.

Keywords

• gastric cancer
• plasma metabolites
• mendelian randomization
• l-aspartic acid