Plasma Proteomics Identifies Proteins and Pathways Associated with Cataract: A Prospective Cohort Study

To systematically identify plasma proteins associated with cataract development and explore their potential causal relationships. Design: Prospective population-based cohort study with integrated Mendelian randomization (MR) and colocalization analyses. Participants: Forty-nine thousand, five hundred and eighty-one UK Biobank participants free of cataract at baseline.

Cox proportional hazards models were used to assess associations between 2920 plasma proteins and cataract risk, followed by MR to evaluate causal relationships. Colocalization analysis was conducted to examine whether identified protein-cataract associations shared causal genetic variants. Main Outcome Measures: Incident cataract.

Of the 2920 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). Mendelian randomization analysis provided evidence supporting causal relationships for 4 proteins (CRYBB2, V-set and immunoglobulin domain-containing protein 4, mevalonate kinase, and metalloproteinase inhibitor 1) 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.

This 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.

The author has no/the authors have no proprietary or commercial interest in any materials discussed in this article.