• Qinglu Fan, Jing Wang, Miao Tian, Abdulla Sawut, Di Xiao, Zuohuizi Yi, and Liao Chen.
• Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People's Republic of China.
• Medicine (Baltimore). 2025 Jan 24; 104 (4): e41331e41331.

AbstractColorectal cancer (CRC) is one of the most common cancers worldwide and inflammation is believed to play an important role in CRC. In this study, we comprehensively analyzed the causal association between 91 circulating inflammatory cytokines and the risk of CRC using Mendelian randomization (MR). Based on genome-wide association study summary statistics, we examined the causal effects of 91 circulating inflammatory cytokines on CRC. A series of MR methods, including bidirectional MR, replication sample MR, and multivariable MR, were employed to provide more robust causal estimates. After the validation with 3 MR methods and a series of sensitivity analyses, 2 circulating inflammatory factors were found to be significantly associated with the risk of CRC at the genetic level. Specifically, genetically predicted circulating levels of glial cell line-derived neurotrophic factor (GDNF) (OR = 1.12; 95% CI: 1.05-1.19; P = 2.72 × 10-4) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (OR = 0.93; 95% CI: 0.91-0.99; P = 1.00 × 10-2) exerted causal effects on CRC risk. In conclusion, this study suggests that increased circulating levels of GDNF and TRAIL are associated with a higher and lower risk of CRC, respectively. GDNF and TRAIL may be 2 potential therapeutic targets that deserve future investigation.Copyright © 2025 the Author(s). Published by Wolters Kluwer Health, Inc.

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