Mendelian randomization analysis of metabolic blood biomarkers and gastrointestinal cancer risk

BACKGROUND: Gastrointestinal (GI) cancers remain among the most lethal malignancies worldwide, highlighting the need for novel insights into modifiable risk factors. Blood-based metabolic biomarkers - routinely measured in clinical settings - may play a role in cancer etiology, but their causal impact remains unclear. OBJECTIVES: This study aimed to explore the causal relationship between metabolic blood biomarkers and the risk of GI cancers using Mendelian randomization (MR). MATERIAL AND METHODS: We conducted an MR analysis using large-scale genome-wide association study (GWAS) data to evaluate the causal effects of metabolic blood traits (e.g., low-density lipoprotein (LDL) cholesterol, creatinine, uric acid, total protein, and total cholesterol) on the risk of 4 major GI cancers: gastric, colorectal, pancreatic, and gallbladder cancer. Statistical robustness was evaluated using the MR-PRESSO test and Cochran's Q test. RESULTS: Mendelian randomization analysis revealed several significant associations. Low-density lipoprotein cholesterol was inversely associated with gastric cancer risk (odds ratio (OR) = 0.815, 95% confidence interval (95% CI): 0.703-0.946, p < 0.01), while total cholesterol also showed a protective effect (OR = 0.790, 95% CI: 0.693-0.900, p < 0.01). Serum creatinine levels were strongly associated with a reduced risk of gallbladder cancer (OR = 0.037, 95% CI: 0.005-0.287, p < 0.01). Higher serum total protein (OR = 0.855, 95% CI: 0.777-0.940, p < 0.01) and uric acid levels (OR = 0.855, 95% CI: 0.769-0.951, p < 0.01) were associated with a reduced risk of colorectal cancer (CRC). Serum uric acid levels were also associated with a reduced risk of gastric cancer (OR = 0.822, 95% CI: 0.719-0.941, p < 0.01), but with an increased risk of pancreatic cancer (OR = 1.246, 95% CI: 1.01-1.539, p = 0.040). CONCLUSIONS: Our findings provide causal evidence linking common metabolic blood biomarkers to site-specific GI cancer risks. These results may inform biomarker-based risk stratification and preventive strategies in oncology and public health.