Mendelian Randomization Analyses of Genetically Predicted Circulating Levels of Cytokines with Risk of Inflammatory Bowel Disease

Objective The literature has previously reported the associations between inflammatory bowel disease (IBD) and certain inflammatory cytokines, such as CRP, IL-1, and TNFα. To additionally evaluate the causal relationships between 41 inflammatory cytokines and IBD, a Mendelian randomization (MR) study was conducted. Methods The two-sample MR investigation utilized data from three large publicly available genome-wide association studies (GWAS) on IBD, ulcerative colitis (UC), and Crohn's disease (CD) genetic variants. Additionally, inflammatory cytokine data from a GWAS meta-analysis, including 8,293 healthy individuals, were incorporated into the study. Causal relationships between exposures and outcomes were predominantly determined utilizing inverse variance-weighted methods. To evaluate the heterogeneity, pleiotropy, and stability of these genetic variants, the MR-Egger intercept test, Cochran's Q test, and leave-one-out sensitivity analysis were conducted. Results The findings revealed that IL13 was linked to an elevated risk of IBD, UC, and CD, while MIF demonstrated a correlation with an elevated risk of CD. Conversely, TNF-related apoptosis-inducing ligand (TRAIL) was linked to a decreased risk of IBD and UC. Additionally, reverse MR analyses revealed that IBD was correlated with elevated levels of Monokine Induced by Gamma Interferon (MIG) and Stromal Cell-Derived Factor-1α (SDF1A), while UC showed an association with elevated levels of MIG and IL10. The CD was linked to elevated levels of stem cell factor (SCF) and decreased levels of TNF-β. Conclusion In the MR study, three upstream regulatory factors and five downstream regulatory factors were identified for IBD and its subtypes, providing avenues for developing new therapies for IBD.