Genetic susceptibility and clinical validation of ICAM-5 in immune-mediated non-infectious uveitis

Purpose To investigate genetically supported molecular factors associated with uveitis and to evaluate the clinical, transcriptomic, and retinal relevance of intercellular adhesion molecule 5 (ICAM-5) across major immune-mediated non-infectious uveitis subtypes. Methods Two-sample Mendelian randomization (MR) was conducted using eQTLGen eQTL data and two independent pQTL resources (Icelandic SomaScan and FinnGen R10), with uveitis GWAS summary statistics as the outcome. ICAM5 was evaluated using complementary MR estimators, sensitivity analyses, reverse MR, and Bayesian colocalization. Plasma ICAM-5 concentrations were measured by ELISA in 90 patients with active non-infectious uveitis (30 each with Vogt-Koyanagi-Harada disease, Behçet’s disease-associated uveitis, and HLA-B27-associated acute anterior uveitis) and 40 healthy controls using age- and sex-adjusted models. ICAM5 expression was further examined in the peripheral-blood transcriptomic dataset GSE194060, whereas retinal Icam5 expression and cellular distribution were evaluated using experimental autoimmune uveitis retinal single-cell RNA-sequencing data and GSE132229. Results Genetically predicted higher ICAM5 expression and ICAM-5 protein levels were associated with increased uveitis susceptibility in the eQTLGen dataset (OR = 2.46, 95% CI 1.48–4.11, P = 5.69 × 10 -4 ; nSNP =8), the Icelandic SomaScan cis-pQTL analysis (OR = 1.27, 95% CI 1.11–1.46, P = 5.30 × 10 -4 ; nSNP =89), and the FinnGen R10 cis-pQTL analysis (OR = 1.21, 95% CI 1.07–1.38, P = 3.13 × 10 - ³; nSNP =4). Sensitivity analyses showed no significant heterogeneity or horizontal pleiotropy, and reverse MR provided no evidence of an association from uveitis liability to ICAM-5 levels. Plasma ICAM-5 concentrations were higher in all three uveitis subgroups than in healthy controls and remained elevated after age and sex adjustment, with the greatest increase in Vogt-Koyanagi-Harada disease. In the GSE194060 peripheral-blood transcriptomic dataset, ICAM5 expression was higher in the uveitis group. Analysis of the retinal single-cell RNA-sequencing data showed that Icam5 was predominantly detected in neuronal populations. Conclusion Multi-omics MR, clinical protein quantification, transcriptomic analysis, and retinal single-cell profiling provide convergent evidence linking ICAM-5 to immune-mediated non-infectious uveitis. These findings support ICAM-5 as a genetically supported candidate mediator and circulating biomarker.