Relationship of Between Metabolic Risk Factors and Digestive System Cancers in East Asian Populations: Two-Sample and Multivariable Mendelian Randomization Analyses

Background: 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. Our objective was to explore the causal associations between genetically predicted metabolic risk factors and DSCs.Methods: We performed univariable and multivariable Mendelian randomization analyses to systematically explore the associations between 21 metabolic risk factors and DSCs, including esophageal, gastric, colorectal, hepatocellular, biliary tract, and pancreatic cancer. We categorized there 21 risk factors were categorized into four groups: lifestyle factors, physical factors, serum parameters, and metabolic comorbidities. MR-Egger regression, weighted median, inverse variance weighted (IVW), and weighted mode methods were used to evaluate the potential causal associations. We also checked the robustness of the IVW estimates using the leave-one-out sensitivity test.Findings: 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. We found no significant associations between HbA1c and gastric and pancreatic cancers after adjusting for genetically predicted type 2 diabetes. Additionally, there was no evidence for a causal association between other metabolic risk factors, including body mass index, waist circumference, waist-to-hip ratio, educational levels, fasting plasma glucose, lipoprotein cholesterol, total cholesterol, glycine, creatinine, gout, and Graves’ disease, and DSCs. The single nucleotide polymorphism rs671 from the ALDH2 gene interfered with the robustness of the Mendelian randomization results.Interpretion: The present study showed that genetically predicted alcohol drinking was a strong indicator of gastric cancer and hepatocellular carcinoma, and demonstrated a suggestive causal association between coffee consumption and hepatocellular carcinoma, triglyceride and biliary tract cancer, uric acid and pancreatic cancer, and MetS and esophageal and gastric cancer development.Funding: This work was supported by the Natural Science Foundation of Zhejiang Province (LQ21H160013), the Medical Science and Technology Project of Zhejiang Province (2022KY1104, 2023KY1033, and 2023KY236), and the Natural Science Foundation of Ningbo (2022J264).Declaration of Interest: The authors declare no conflict of interest.Ethical Approval: The analyses were approved by the Institutional Ethics Committee in Ningbo Medical Center Lihuili Hospital (KY2022SL264-01).