Abstract
OBJECTIVES: The incidence and mortality of colorectal carcinoma (CRC) continue to rise globally, highlighting the need to identify modifiable risk factors for early detection and prevention. Previous studies have demonstrated significant associations between CRC risk and various serum metabolites as well as inflammatory cytokines; however, due to limitations in study design and potential confounding factors, the causal relationships remain unclear. This study aims to investigate the causal relationships between inflammatory cytokines, serum metabolites, and CRC risk, providing a theoretical basis for the development of novel early diagnostic biomarkers and therapeutic targets. METHODS: A two-sample Mendelian randomization (MR) design was applied using summary statistics from genome-wide association studies (GWAS). Instrumental variables (IVs) were derived from: 1) metabolomics GWAS data of 1 400 serum metabolites (n=8 299); 2) cytokine GWAS data of 91 inflammatory factors (n=14 824); and 3) CRC risk data from the FinnGen consortium (6 847 cases and 314 193 controls). The primary analysis was conducted using the inverse-variance weighted (IVW) method, with sensitivity analyses performed using MR Egger regression and the weighted median method. Effect estimates including odds ratios (OR), 95% confidence intervals (CI), and false discovery rates (FDR) were calculated. RESULTS: MR analysis indicated that higher levels of axin-1 (AXIN1) (OR=0.841 95% CI 0.714 to 0.991) and Fms-related tyrosine kinase 3 ligand (Flt3L) (OR=0.916, 95% CI 0.844 to 0.994) were associated with a reduced risk of CRC. In contrast, higher levels of Delta/Notch- like epidermal growth factor-related receptor (DNER) (OR=1.119, 95% CI 1.009 to 1.241) and vascular endothelial growth factor A (VEGF-A) (OR=1.078, 95% CI 1.011 to 1.150) were associated with an increased risk of CRC (all P<0.05). Metabolomics association analysis further identified 144 serum metabolites significantly correlated with these four key inflammatory cytokines (FDR<0.05), suggesting that they may regulate CRC risk through inflammatory pathways. CONCLUSIONS: Specific inflammatory cytokines and serum metabolites have causal relationships with the risk of CRC. These findings provide insights for further exploration of potential risk factors and the development of effective prevention strategies for CRC.