A large-scale genome-wide and multi-omics investigation into the causality, shared genetic architecture, and gut microbiota feature linking diabetes to iridocyclitis

Diabetes, a pervasive chronic disease that dysregulates glucose metabolism, presents an intricate web of systemic inflammatory complications. Clinical observations have suggested an association between diabetes and iridocyclitis (anterior uveitis, the most prevalent form of uveitis in European countries). Yet this relationship remains controversial and poorly understood, lacking robust evidence from large-scale data. In this study, we used data from multiple large-scale Genome-Wide Association Studies to investigate the causal relationship between type 1 diabetes (T1D) (odds ratio per 2-fold increase in T1D incidence = 1.057, P MR = 1.36 × 10 –42 ; P LDSC = 0.02) and type 2 diabetes (T2D) ( P MR = 0.639; P LDSC = 0.47) with iridocyclitis. Through multi-omics data, we explored the shared genetic architecture of T1D and iridocyclitis at the levels of DNA, methylation, transcriptomics, proteomics and metagenomics. For T1D-iridocyclitis, we prioritized four pleiotropic genes (e.g., PRCC and FUT2 ) and a shared gut microbiota feature ( Parabacteroides ) that contribute to the pathogenesis of both conditions. For T2D-iridocyclitis, no such high-level pleiotropic evidence was observed. Finally, through univariable and multivariable Mendelian randomization, we investigated the relationship between diabetes-free glycemic phenotypes and iridocyclitis. We found that genetically predicted relatively higher fasting insulin and lower two-hour glucose levels were associated with a reduced risk of iridocyclitis. Overall, this study elucidates the causal link between diabetes and iridocyclitis, providing insight into their shared molecular mechanisms and potential avenues for preventive clinical strategies, and drawing attention to the often-overlooked clinical entity of “Type 1 diabetes-related iridocyclitis”.