Plasma proteomics identifies proteins and pathways associated with cataract: a prospective cohort study

Background
Understanding proteomic alterations preceding cataract onset could provide crucial insights into disease mechanisms and reveal novel targets for intervention. This study aims to systematically identify plasma proteins associated with cataract development and explore their potential causal relationships.
Methods
In this prospective analysis of 49,581 UK Biobank participants free of cataract at baseline, 6,199 developed cataract during a median follow-up of 14.05 years. We employed Cox proportional hazards models to assess associations between 2,920 plasma proteins and cataract risk, followed by Mendelian randomization (MR) to evaluate causal relationships. Colocalization analysis was conducted to examine whether identified protein-cataract associations shared causal genetic variants.
Results
Of the 2,920 plasma proteins analyzed, 58 demonstrated significant associations with cataract risk (P < 1.71×10-5, Bonferroni-corrected threshold). Beta-crystallin B2 (CRYBB2) showed the most robust association (hazard ratio: 1.60; 95% confidence interval: 1.55-1.66, P = 5.28×10-164). MR analysis provided evidence supporting causal relationships for four proteins (CRYBB2, VSIG4, MVK, and TIMP1) with cataract, with genetically predicted CRYBB2 levels showing a significant association with cataract risk, which is strongly supported by colocalization evidence. Functional enrichment analyses revealed involvement of biological pathways related to immune activation, cell fate decision, and structural remodeling, in cataract development.ConclusionsThis study identified distinct plasma proteomic signatures associated with incident cataract, offering novel insights into cataract pathogenesis and highlighting potential targets for early detection and therapeutic development.