Abstract
BACKGROUND: Investigations into the association between serum 25-hydroxyvitamin D (25(OH)D) levels and the risk of age-related ocular diseases have yielded inconsistent results. Thus, we aimed to provide robust longitudinal evidence, identify optimal serum thresholds, and explore the underlying mechanisms. METHODS: We analyzed data of 322,953 participants from the UK Biobank. The serum 25(OH)D levels were assessed using chemiluminescent immunoassay. Outcomes were incidences of cataract, primary open-angle glaucoma (POAG), age-related macular degeneration (AMD), and diabetic retinopathy (DR). Hazard ratios and 95% confidence intervals were estimated using Cox proportional hazards models. Nonlinear relationships were explored using restricted cubic splines, and mediation analyses were performed to delineate potential mechanistic pathways. RESULTS: Our findings revealed U-shaped associations for cataract and AMD, and L-shaped associations for DR (all P < 0.05), with an optimal threshold of approximately 50 nmol/L, while no association with POAG was observed. Below this threshold, each 10 nmol/L increase in serum 25(OH)D concentration was linked to a 3.5%, 4.2%, and 6.0% reduction in the risk of cataract, AMD, and DR, respectively (HR 0.965 [95% CI 0.951-0.980]; HR 0.958 [95% CI 0.921-0.997]; HR 0.940 [95% CI 0.894-0.989], respectively), while above 50 nmol/L, no significant protective effects were observed. Mediation analyses revealed that the low-grade inflammation score and triglyceride-glucose index may mediate the effects of serum 25(OH)D on cataract and DR. CONCLUSIONS: This study identified 50 nmol/L as the optimal serum 25(OH)D threshold for reducing risks of cataract, AMD and DR, with no benefits beyond this level. The protective effects may be mediated through modulation of inflammation and glucolipid metabolism pathways. The threshold effects highlight the importance of targeted vitamin D supplementation under careful monitoring of serum levels to optimize ocular health outcomes.