The Causal Relationship between Circulating Metabolic Biomarkers and Gastric Cancer: A Mendelian Randomization Study

Background: Gastric cancer (GC) is a major global health concern, and understanding its etiology is crucial for developing effective prevention strategies.Metabolites, as key intermediates in metabolic pathways, may play a significant role in cancer development.This study employs a Mendelian randomization approach to explore the causal relationship between circulating metabolic biomarkers and the risk of gastric cancer.Methods: An extensive two-sample MR analysis was enrolled in this study.Briefly, the publicly available genetic data were utilized for investigation of the causal association between 233 metabolites and GC; the inverse variance weighted (IVW) model and weighted medians were employed for MR analyses; and sensitivity analyses were adopted for heterogeneity and pleiotropy assessments.Results: Our analysis revealed a total of 49 circulating metabolic biomarkers associated with GC.Of them, Cholesteryl esters to total lipids ratio in large HDL [odds ratio (OR) = 1.850, 95% confidence interval (CI) = 1.264-2.709,P adjusted (P_FDR) = 0.010], Free cholesterol to total lipids ratio in medium LDL (OR = 1.621, 95% CI=1.222-2.150,P_FDR = 0.008), Phospholipids to total lipids ratio in medium LDL (OR = 1.556, 95% CI= 1.193 -2.030, P_FDR= 0.008), Total cholesterol levels in small HDL (OR = 0.472, 95% CI= 0.302 -0.739, P_FDR= 0.008), Cholesterol esters in small HDL (OR = 0.574, 95% CI= 0.391 -0.843, P_FDR= 0.024), and Phospholipids to total lipids ratio in large HDL (OR = 0.580, 95% CI= 0.416 -0.809, P_FDR= 0.009) were strongly associated with GC.Notably, Cholesteryl esters to total lipids ratio in large HDL, Free cholesterol to total lipids ratio in medium LDL, and Phospholipids to total lipids ratio in medium LDL were linked to increased risk factors of GC, while Total cholesterol levels in small HDL, Phospholipids to total lipids ratio in large HDL, Cholesterol esters in small HDL, and Phospholipids to total lipids ratio in large HDL are the protective factor of GC. Conclusion:This study provides evidence for a causal relationship between circulating metabolic biomarkers and gastric cancer, emphasizing the importance of metabolic factors in cancer etiology.Our findings contribute to the understanding of gastric cancer mechanisms and may inform future research on prevention and treatment strategies.Further studies are warranted to validate these associations and explore CS 5 (1),