Abstract
Background: Metabolic dysregulation is increasingly recognized as a systemic process contributing to chronic disease development, yet prospective evidence linking integrated metabolic vulnerability to age-related eye diseases remains limited. We investigated whether a biomarker-based metabolic vulnerability index (MVX) was associated with incident age-related ocular diseases and whether joint consideration of MVX and genetic susceptibility may help characterize relative risk patterns.</p>
Methods: A prospective population-based cohort of 206,311 participants from the UK Biobank was analyzed. MVX was evaluated as the primary exposure. Incident age-related macular degeneration (AMD), cataract, diabetic retinopathy (DR), and glaucoma were ascertained as outcomes. Associations were examined using Cox proportional hazards models, with hazard ratios (HRs) and 95% confidence intervals (CIs) estimated per 1-standard deviation (SD) increase in MVX. As secondary exploratory analyses, polygenic risk score (PRS) analyses were performed to explore whether metabolic vulnerability and genetic susceptibility jointly characterized relative risk patterns.</p>
Results: During follow-up, 4,144 participants developed AMD, 13,574 cataract, 1,483 DR, and 5,525 glaucoma. After multivariable adjustment for demographic, socioeconomic, clinical, and lifestyle factors, each 1-SD increase in MVX was associated with higher risks of incident AMD (HR = 1.07; 95% CI: 1.03-1.11), cataract (HR = 1.04; 95% CI: 1.02-1.06), and DR (HR = 1.11; 95% CI: 1.05-1.18), whereas no significant association was observed for glaucoma (HR = 1.00; 95% CI: 0.97-1.03). In joint analyses, individuals with both high genetic risk and elevated MVX exhibited the greatest risks of AMD (HR = 2.32; 95% CI: 2.01-2.67), cataract (HR = 1.62; 95% CI: 1.49-1.76), and DR (HR = 3.84; 95% CI: 2.91-5.06), compared with those with low genetic risk and low MVX.</p>
Conclusion: These findings suggest that MVX may be relevant to population-level patterns of risk for several age-related eye diseases. However, further studies are needed to determine whether MVX provides meaningful predictive value or clinical utility beyond conventional risk factors.</p>