Metabolic factors play a critical role in the development of
digestive system cancers (DSCs), and East Asia has the highest incidence of malignant
tumors in the digestive system. We performed a two-sample Mendelian randomization analysis to explore the associations between 19 metabolism-related lifestyle and clinical risk factors and DSCs, including esophageal, gastric, colorectal, hepatocellular, biliary tract, and
pancreatic cancer. The causal association was explored for all combinations of each risk factor and each DSC. We gathered information on the instrumental variables (IVs) from various sources and retrieved outcome information from Biobank Japan (BBJ). The data were all from studies of east Asian populations. Finally, 17,572 DSCs cases and 195,745 controls were included. Our analysis found that genetically predicted alcohol drinking was a strong
indicator of
gastric cancer (odds ratio (OR) = 0.95; 95% confidence interval (CI): 0.93-0.98) and
hepatocellular carcinoma (OR = 1.11; 95% CI: 1.05-1.18), whereas
coffee consumption had a potential protective effect on
hepatocellular carcinoma (OR = 0.69; 95% CI: 0.53-0.90).
Triglyceride was potentially associated with a decreased risk of
biliary tract cancer (OR = 0.53; 95% CI: 0.34-0.81), and
uric acid was associated with
pancreatic cancer risk (OR = 0.59; 95% CI: 0.37-0.96).
Metabolic syndrome (MetS) was associated with esophageal and
gastric cancer. Additionally, there was no evidence for a causal association between other risk factors, including body mass index, waist circumference, waist-to-hip ratio, educational levels,
lipoprotein cholesterol, total
cholesterol,
glycine,
creatinine,
gout, and
Graves' disease, and DSCs. The leave-one-out analysis revealed that the single nucleotide polymorphism (SNP) rs671 from the ALDH2 gene has a disproportionately high contribution to the causal association between alcohol drinking and
gastric cancer and
hepatocellular carcinoma, as well as the association between
coffee consumption and
hepatocellular carcinoma. The present study revealed multiple metabolism-related lifestyle and clinical risk factors and a valuable SNP rs671 for DSCs, highlighting the significance of metabolic factors in both the prevention and treatment of DSCs.