Metabolic vulnerability, genetic susceptibility, and incident age-related eye diseases: a prospective cohort study

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.

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.

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.

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.