A Bidirectional Mendelian Randomization Analysis of Circulating Inflammatory Cytokines with Colon and Rectum Cancers

Abstract

Chronic inflammation has been proposed to be associated with tumor development and progression. Dynamic changes in serum cytokines induced by feedback mechanisms from tumors make differentiation of cause and effect difficult. In this study, a bidirectional summary-level Mendelian randomization (MR) analysis was performed to elucidate the causal correlation between inflammatory regulators with colon (CC) and rectum (RC) carcinomas. Summary-level data on inflammation-related genetic variations were extracted from a genome-wide association meta-analysis. Corresponding data for CC and RC were obtained from the FinnGen (CC: 1396 cases vs. 174,006 controls; RC: 1,078 cases vs. 174,006 controls) and UK Biobank (CC: 2,226 cases vs. 358,968 controls; RC: 1,170 cases vs. 360,024 controls) consortiums. Inverse-variance weighted MR was used as the primary method, and sensitivity analysis was performed to assess the MR assumptions. After P value correction and meta-analysis, there was evidence of direct associations between macrophage migration inhibitory factor (MIF) and CC (95% confidence interval (CI):1.001-1.003; P = 8.77×10-4) and inverse correlations between Interleukin-17 (IL-17) and RC (95% CI: 0.997-0.999; P = 1.15×10-3). Conversely, interleukin-1 receptor antagonist (IL1ra) was downregulated in patients at a higher risk of RC (P = 0.006), and no reliable results revealed a causal association between other cytokines and CC and RC. Thus, this MR study suggests that downregulated serum MIF and elevated serum IL-17 concentrations may reduce the risk of CC and RC, respectively. Therefore, MIF and IL-17 may serve as potential therapeutic targets, and further exploration of their underlying mechanisms is warranted.