Causal relationship between inflammatory factors and inflammatory bowel disease: A bidirectional Mendelian randomization study combined with meta-analysis

Abstract

Due to the limitations of traditional observational studies, investigating the association between inflammatory factors and inflammatory bowel disease (IBD) remains challenging. In this study, we employed Mendelian randomization (MR) combined with meta-analysis to assess the causal relationship between 91 inflammatory factors and IBD. We selected genome-wide association study (GWAS) data for inflammatory factors and IBD from GWAS databases and conducted 2-sample MR analyses using the inverse-variance weighted (IVW) method, MR-Egger regression, and weighted median estimator. The MR analyses were performed for 91 inflammatory factors with IBD outcome data from 2 different databases. Subsequently, a meta-analysis of the main IVW results was conducted, followed by multiple corrections of the meta-analysis results. Conduct MR analysis between inflammatory factors and subtypes of IBD (Crohn disease and ulcerative colitis [UC]), followed by reverse causality validation of positive inflammatory factors with IBD and its subtype outcome data. In the IVW analysis of the 91 inflammatory factors with IBD outcome data from the GWAS catalog database, C-X-C motif chemokine 9 (CXCL9) was found to be positively associated with the risk of IBD (OR = 1.24, 95% CI = 1.09-1.41, P = .001). Similarly, in the IVW analysis with IBD outcome data from the IEU database, CXCL9 was also positively associated with the risk of IBD (OR = 1.76, 95% CI = 1.12-2.76, P = .015). Meta-analysis and multiple corrections showed a significant association between CXCL9 and IBD (OR = 1.27, 95% CI = 1.12-1.44, P = .001). In the MR analysis of IBD subtypes, the inflammatory factor CXCL9 showed a significant causal association with UC using the IVW method (OR = 1.77, 95% CI = 1.39-2.44, P = .0004), with a P-value of .038 after multiple testing correction. However, no significant causal association was observed between CXCL9 and Crohn disease = 3.28). In the reverse MR analysis, no causal effect of IBD and UC on CXCL9 was found. CXCL9 exhibits a causal relationship with IBD, functioning as a disease-progression risk factor that elevates UC risk, suggesting potential therapeutic targets for alleviating symptoms and slowing progression in UC patients.

Keywords: bidirectional Mendelian randomization analysis; inflammatory bowel disease; inflammatory factors; meta-analysis; multiple corrections.

Figure 1.

Mendelian randomization combination chart of C-X-C motif chemokine 9 on IBD (GWAS catalog). GWAS = genome-wide association study, IBD = inflammatory bowel disease.

Figure 2.

Mendelian randomization combination chart of C-X-C motif chemokine 9 on IBD (IEU).

Figure 3.

Forest plot of C-X-C motif chemokine 9 after meta-analysis and multiple corrections.