Decoding ulcerative colitis: Plasma protein-mediated antibody immune responses influence disease risk.

OBJECTIVE

Previous Mendelian randomization (MR) studies have explored the role of plasma proteins in ulcerative colitis (UC), but the underlying mechanisms, particularly how plasma proteins influence UC risk via immune-mediated pathways, remain unclear. This study integrates two-sample MR and mediation analysis to investigate whether plasma proteins influence UC risk through antibody-mediated immune responses, aiming to identify novel biomarkers and therapeutic targets.

METHODS

We analyzed 4907 plasma proteins from a genome-wide association study, 46 immune antibody responses, and UC data from the FinnGen consortium. Two-sample MR was used to assess causal relationships among plasma proteins, antibody responses, and UC. Mediation MR analysis was conducted to evaluate whether specific antibody responses mediate the effect of plasma proteins on UC risk.

RESULTS

A total of 80 plasma proteins with significant causal associations with UC were identified (P < 0.05). Two antibody responses, Epstein-Barr virus (EBV) EA-D antibody levels and anti-HSV-1 IgG seropositivity, were significantly and inversely associated with UC risk (EBV: OR = 0.794, 95 % CI: 0.646-0.974, P = 0.027; HSV-1 IgG: OR = 0.891, 95 % CI: 0.801-0.992, P = 0.035). Five plasma proteins showed significant causal effects on these antibody responses: UBC, TIMD4, and NEFL (linked to EBV EA-D), and TMEM70 and HIF1A (linked to HSV-1 IgG). Mediation analysis revealed that antibody responses explained 9.2 %-13.2 % of the total effects of these proteins on UC risk. For example, UBC increased UC risk partially through reduced EBV EA-D antibodies (mediated effect = 0.0588), while HIF1A contributed to UC risk via suppressed HSV-1 IgG seropositivity.

CONCLUSION

This study identifies a novel immuno-genetic pathway in UC pathogenesis, where specific plasma proteins influence disease risk through modulation of viral antibody responses. These findings suggest potential targets, such as UBC, HIF1A, and TIMD4, for biomarker development and immune-focused interventions in UC.