Introduction
Graves’ disease (GD) and ulcerative colitis (UC) are two distinct autoimmune disorders with increasing evidence of shared pathophysiological mechanisms. While previous epidemiological studies have reported a higher risk of IBD among individuals with GD, the association between GD and UC specifically remains controversial. In particular, the causal direction, genetic liability, and molecular mediators underlying this relationship are not well defined.
Aims & Methods
We conducted a multi-layered investigation to clarify the relationship between GD and UC. First, a large-scale prospective analysis using the UK Biobank cohort was performed to assess the association between GD and subsequent UC risk, with adjustments for demographic, lifestyle, and clinical covariates utilizing COX proportional hazard models. Second, two-sample Mendelian randomization (MR) analyses were conducted using publicly available genome-wide association study (GWAS) datasets to infer potential causal links. Finally, we performed protein mediation analysis integrating plasma proteomic data to identify potential intermediate proteins and pathways mediating the effect of GD on UC.
Results
Observational analysis revealed that patients with GD had a significantly elevated risk of developing UC. Stratified analysis further revealed that this association was more pronounced among male and obese individuals. The association remained significant even after adjusting for key covariates including medication use, psychological disorders, air pollution exposure, and sunlight exposure. Genetic-level analysis using Mendelian randomization confirmed a potential causal relationship between AITD and UC. This association was independently validated in MR sensitivity analyses. Through mediation analysis based on plasma proteomic data, 28 UC-related proteins were identified as potential mediators of the AITD–UC relationship. Among them, proteins such as Arachidonate 15-lipoxygenase B (ALOX15B) were significantly enriched in the high-risk group. Collectively, six pathways likely represent the core signaling axes through which GD promotes UC pathogenesis, highlighting potential targets for mechanistic and therapeutic exploration.
Conclusion
This study provides robust clinical, genetic, and molecular evidence for a link from GD to UC, mediated through specific immunopathogenic proteins and pathways. These findings offer novel insights into shared autoimmunity and may inform biomarker-driven strategies for early identification and targeted prevention of UC in patients with GD.
References
Ferrari SM. The association of other autoimmune diseases in patients with Graves' disease (with or without ophthalmopathy): Review of the literature and report of a large series. Autoimmun Rev. 2019 Mar;18(3):287-292.
Ordás I. Ulcerative colitis. Lancet. 2012 Nov 3;380(9853):1606-19.
Xian W. Graves Disease and Inflammatory Bowel Disease: A Bidirectional Mendelian Randomization. J Clin Endocrinol Metab. 2023 Apr 13;108(5):1075-1083.
Burisch J. Incidence of Immune-Mediated Inflammatory Diseases Among Patients With Inflammatory Bowel Diseases in Denmark. Clin Gastroenterol Hepatol. 2019 Dec;17(13):2704-2712.e3.
Disclosure
The authors declare no conflicts of interest.