Mendelian randomization analyses of genetically predicted circulating levels of cytokines with risk of Inflammatory bowel disease

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Abstract 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.

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