Assessment of the relationship between colorectal cancer and systemic inflammatory regulators: a bidirectional Mendelian randomization study

Abstract

Abstract Background Inflammation is intricately intertwined with cancer progression; however, the causal link between inflammatory factors and their propensity to either promote or mitigate colorectal cancer (CRC) remains substantively unexplored. In response to this knowledge gap, we undertook a bidirectional Mendelian randomization (MR) analysis, aimed at rigorously evaluating the causal relationship between 41 distinct genetic proxies representing inflammatory factors and the development of colorectal cancer. Method Cytokine levels were analyzed in a cohort of 8,293 individuals using data from a genome-wide association study (GWAS) focusing on exposures. Preliminary analysis made use of GWAS data related to colorectal cancer (CRC) obtained from the GWAS catalog database with accession number GCST012879. Causality analysis primarily employed the random inverse variance weighted (IVW) method, supplemented by MR-Egger and weighted median techniques. To enhance the study's robustness, sensitivity analyses encompassed the Cochran Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis. Employing a comprehensive approach encompassing Mendelian Randomization, Linkage Disequilibrium Score Regression, and Colocalization Analysis, the study examined cytokines that exhibited statistical significance in the IVW analysis. Moreover, a Confounding Analysis was conducted to evaluate the direct impact of cytokines on CRC occurrence. Result The findings of this study demonstrate a significant association between Interferon-gamma (OR = 1.13, 95% CI = 1.01–1.28, p = 0.039), Tumor Necrosis Factor-beta (OR = 1.07, 95% CI = 1.01–1.14, p = 0.032), Interleukin-2 Receptor Alpha Subunit (OR = 0.93, 95% CI = 0.86–0.99, p = 0.035), and Stem Cell Factor (OR = 0.88, 95% CI = 0.79–0.98, p = 0.023) and CRC. Conclusion This study presents compelling evidence regarding the causal interplay between four specific inflammatory factors and colorectal cancer. Furthermore, the multifaceted analyses employed introduce fresh insights into our understanding of the role played by colorectal cancer. These discoveries hold promising implications for enhancing CRC screening, prevention, and therapeutic strategies.