Genetic predisposition to systemic inflammatory proteins is causally associated with inflammatory bowel disease:...

Systemic inflammatory proteins have been reported to be related to inflammatory bowel disease (IBD) in previous observational research. However, their causal links remain obscure. Herein, we performed a Mendelian randomization (MR) analysis to analyze the causality between systemic inflammatory proteins and IBD. Genetic variants related to systemic inflammatory proteins were extracted from a meta-analysis of genome-wide association study (GWAS) data of 8293 European participants. Summary statistics of IBD diverse subtypes were obtained from the international IBD genetic consortium (IIBDGC). We conducted multi-omics method and MR study to detect the causal links through integrating GWAS and protein quantity trait loci (pQTL) data. Inverse variance weighted (IVW) approach was utilized as the dominated analysis method. Moreover, complementary approaches such as MR-Egger intercept test, Cochran Q test and leave-one-out analysis were utilized to validate pleiotropy and heterogeneity. Finally, single-cell RNA-sequencing analysis was performed to detect the expression of significant genes. For IBD, IVW estimates suggested that genetically predicted IL-10 and IL-13 were suggestively associated with an elevated risk of IBD (IL-10: OR: 1.12, 95% CI: 1.00-1.24, P = .04; IL-13: OR: 1.09, 95% CI: 1.01-1.18, P = .023), while CXCL10 was suggestively linked to a lower risk of IBD (CXCL10: OR: 0.90, 95% CI: 0.82-0.99, P = .037). For Crohn disease (CD), the IVW approach provided evidence to sustain that genetically determined IL-13 and CCL3 had a suggestive association with a higher risk of CD (IL-13: OR: 1.13, 95% CI: 1.02-1.26, P = .023; CCL3: OR: 1.22, 95% CI: 1.03-1.45, P = .018). Sensitivity analysis did not explore any heterogeneity and pleiotropy. Our findings supported the causal relationships between 4 specific inflammatory proteins (IL-10, IL-13, CXCL10, and CCL3) and the risk of IBD and CD, thereby providing promising biomarkers of various subtypes stratification and new insights for the prevention and therapeutic target of IBD.