35 blood and urine biomarkers and digestive system cancers: A two-sample Mendelian randomization study

Digestive system cancers (DSCs) are globally prevalent and account for a substantial proportion of cancer-related deaths. This study aimed to investigate the potential causal relationships between 35 blood and urine biomarkers and the risk of 4 major DSCs, including esophageal, gastric, colorectal, and pancreatic cancers. A 2-sample bidirectional Mendelian randomization (MR) approach was employed. Genome-wide association studies (GWAS) summary statistics for DSCs were obtained from public databases, and biomarker data were sourced from a GWAS meta-analysis of the UK Biobank. The inverse variance weighted (IVW), MR-Egger, and weighted median methods were used to examine causality. To evaluate robustness, we performed sensitivity analyses, including Cochran Q test for heterogeneity, MR-Egger and MR-PRESSO tests for pleiotropy, and leave-one-out analysis. Furthermore, reverse MR analyses were conducted for all significant causal relationships identified. We identified 14 significant associations: 6 with esophageal cancer, 1 with gastric cancer, 3 with colorectal cancer, and 4 with pancreatic cancer. Elevated serum uric acid was associated with increased pancreatic cancer risk (odds ratio [OR] = 1.230, 95% confidence interval [CI]: 1.015-1.490, P = .035) but decreased esophageal cancer risk (OR = 0.822, 95% CI: 0.683-0.989, P = .038). Increased insulin-like growth factor (IGF-1) levels were associated with higher risks of esophageal (OR = 1.228, 95% CI: 1.035-1.457, P = .019) and colorectal cancer (OR = 1.216, 95% CI: 1.125-1.314, P < .001). Subsequent sensitivity analyses revealed that our results were rarely influenced by pleiotropy or heterogeneity. Reverse MR analysis indicated that there were no causal associations between genetic predisposition to DSCs and the identified biomarkers. The identified biomarkers may serve as potential diagnostic markers, aiding in the early detection of cancer, which is crucial for improving treatment outcomes.