Causal Association between Iritis or Uveitis and Glaucoma: A Two-Sample Mendelian Randomisation Study

Genes · 2 authors, 2 centres

AI SUMMARY

FIDELITY 100%

POPULATIONEast Asian (Biobank Japan, n=175,653 for iritis, n=174,725 for uveitis) and multi-ethnic (meta-analysis of Biobank Japan and UK Biobank, n=656,395 for iritis, n=655,467 for uveitis) populations; glaucoma outcome data from GERA cohort and UK Biobank (n=240,302; 12,315 cases, 227,987 controls)

INTERVENTIONGenetic predisposition to iritis or uveitis (measured by single-nucleotide polymorphisms associated with these conditions)

COMPARISONNo genetic predisposition to iritis or uveitis

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TL;DR

This Mendelian randomization study provides strong genetic evidence that iritis causally increases the risk of glaucoma in both East Asian and multi-ethnic populations, and uveitis also shows a causal effect in the multi-ethnic population. The findings suggest that the current classifications of uveitic glaucoma and open-angle glaucoma may overlap, highlighting the need for further research into these complex interactions.

Full summary

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**Background:** Uveitis, particularly anterior uveitis (iritis), is an inflammatory eye condition that can lead to glaucoma, a leading cause of irreversible vision loss. Uveitic glaucoma (UG) is a complex disorder where glaucoma coexists with uveitis, but not all uveitis patients develop glaucoma. Previous studies report glaucoma prevalence in uveitis ranging from 11–20% after 5 years. The pathogenesis of UG involves intraocular pressure (IOP) elevation due to trabecular meshwork changes or angle closure. Both uveitis and glaucoma have genetic predispositions, with uveitis strongly linked to human leukocyte antigen (HLA) genes. This study aimed to investigate the causal relationship between iritis or uveitis and glaucoma using two-sample Mendelian randomization (MR) analysis, leveraging large genetic datasets from East Asian and multi-ethnic populations.

**Methods:** The study used summary statistics from genome-wide association studies (GWAS) for iritis and uveitis from Biobank Japan (BBJ) for East Asians (n=175,653 for iritis; n=174,725 for uveitis) and a meta-analysis of BBJ and UK Biobank (UKB) for multi-ethnic populations (n=656,395 for iritis; n=655,467 for uveitis). Glaucoma outcome data came from a meta-analysis of the GERA cohort and UKB (n=240,302; 12,315 open-angle glaucoma [OAG] cases, 227,987 controls). Single-nucleotide polymorphisms (SNPs) associated with iritis and uveitis at genome-wide significance (p < 5.0 × 10⁻⁸) were used as instrumental variables (IVs); when insufficient, a threshold of p < 5.0 × 10⁻⁴ was applied. SNPs were clumped for linkage disequilibrium (R² < 0.001, 10,000 kb window) using the 1000 Genomes East Asian reference panel. F-statistics were calculated to assess IV strength (all >10, indicating low weak instrument bias). The primary MR analysis used inverse-variance weighted (IVW) method, with sensitivity analyses including weighted median, MR-Egger, and MR-Egger with Simulation Extrapolation (SIMEX). Heterogeneity was assessed with Cochran's Q and Rücker's Q' tests, and horizontal pleiotropy with MR-PRESSO global and outlier tests.

**Key Results:** For iritis, 2 IVs were identified in East Asians (mean F=41,588) and 11 in the multi-ethnic population (mean F=7,704). For uveitis, 60 IVs were identified in East Asians (mean F=6,433) and 10 in the multi-ethnic population (mean F=8,396). No significant heterogeneity or horizontal pleiotropy was detected (all p > 0.05). In East Asians, iritis showed a significant causal association with glaucoma (IVW MR OR = 1.01, 95% CI: 1.00–1.01, p = 0.017). In the multi-ethnic population, iritis also showed a significant causal association (IVW MR OR = 1.04, 95% CI: 1.01–1.06, p = 0.001; weighted median MR OR = 1.05, 95% CI: 1.02–1.08, p = 0.003; MR-Egger MR OR = 1.05, 95% CI: 1.01–1.09, p = 0.028; MR-Egger SIMEX MR OR = 1.05, 95% CI: 1.02–1.09, p = 0.020). For uveitis, no significant association was found in East Asians (IVW MR OR = 0.9995, 95% CI: 0.9990–1.0000, p = 0.49), likely due to low statistical power. However, in the multi-ethnic population, uveitis showed a significant causal association with glaucoma (IVW MR OR = 1.04, 95% CI: 1.02–1.06, p = 0.001; weighted median MR OR = 1.05, 95% CI: 1.02–1.08, p = 0.003; MR-Egger MR OR = 1.05, 95% CI: 1.01–1.08, p = 0.039; MR-Egger SIMEX MR OR = 1.05, 95% CI: 1.01–1.08, p = 0.034).

**Clinical Implications:** This study provides strong genetic evidence that iritis causally increases the risk of glaucoma in both East Asian and multi-ethnic populations, and uveitis has a causal effect in multi-ethnic populations. The findings suggest that the current classification of uveitic glaucoma and open-angle glaucoma may overlap, as early-stage uveitic glaucoma often presents with open-angle features. The results highlight the importance of considering genetic predisposition in understanding the pathophysiology of uveitic glaucoma and may inform future therapeutic targets, particularly those involving HLA and immune-related genes. However, limitations include the use of summary statistics (precluding adjustment for confounders), the rarity of uveitis and its strong HLA association (which may affect MR assumptions), and the need for cautious interpretation due to potential violation of MR assumptions. Further research is needed to refine disease classification and explore causal mechanisms.