Genetic susceptibility and clinical validation of ICAM-5 in immune-mediated non-infectious uveitis
4 affiliations
- 1Department of Ophthalmology, The Second Affiliated Hospital of Fujian Medical University
- 2Engineering Research Center of Assistive Technology for Visual Impairment, Fujian Provincial Universities
- 3Department of Epidemiology and Biostatistics, School of Public Health, Peking University
- 4Department of Plastic Surgery, The Second Affiliated Hospital of Fujian Medical University
Abstract
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.
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BibTeX
@article{zhuang2026genetic,
title = {{Genetic susceptibility and clinical validation of ICAM-5 in immune-mediated non-infectious uveitis}},
author = {Zihao Zhuang and Pengcheng Hu and Xuanming Hong and Tianfeng Lin and Yang Yu and Xinyu Jia and Xuemei Su and Binling Su and Wenjian Shi and Jianmin Hu},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1948697},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1948697/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Genetic susceptibility and clinical validation of ICAM-5 in immune-mediated non-infectious uveitis
AU - Zihao Zhuang
AU - Pengcheng Hu
AU - Xuanming Hong
AU - Tianfeng Lin
AU - Yang Yu
AU - Xinyu Jia
AU - Xuemei Su
AU - Binling Su
AU - Wenjian Shi
AU - Jianmin Hu
PY - 2026
DA - 2026/10/06
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1948697
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1948697/full
AB - 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.
SN - 1664-3224
ER -