Colorectal 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.

While recent studies suggested a potential causal link between type 1 diabetes mellitus (T1DM) but not type 2 diabetes mellitus (T2DM) and idiopathic pulmonary fibrosis (IPF), the involved mechanism remains unclear. Here, using a Mendelian randomization (MR) approach, we verified the causal relationship between the two types of diabetes mellitus and IPF and investigated the possible role of inflammation in the association between diabetes mellitus and IPF. Based on genome-wide association study (GWAS) summary data of T1DM, T2DM, and IPF, the univariable MR, multivariable MR (MVMR), and mediation MR were successively used to analyze the causal relationship. Inverse variance weighted was used as the main method to infer the causal effect, together with a series of sensitivity analyses. The univariable MR showed that only T1DM increased the risk of IPF, and there was no significant causal relationship between T2DM and IPF. The MVMR further verified that there was an independent direct causal effect of T1DM on IPF. Further mediation analysis showed that this effect was partly mediated by increasing C-X-C motif chemokine ligand 10 (CXCL10) and interleukin-12 subunit beta (IL-12B). In conclusion, T1DM is related to an increased risk of IPF. Notably, the causal effect was partially mediated by CXCL10 and IL-12B. Hence, monitoring T1DM patients may help in the early detection and prevention of IPF.