Abstract
PURPOSE: To investigate the causal relationship between type 1 diabetes (T1D) and cataracts and to explore the mediating role of serum metabolites. METHODS: This study employed bidirectional Mendelian randomization (MR) using genetic variants as instrumental variables to infer causality in both directions: from T1D to cataracts and cataracts to T1D. Genetic data for T1D, its complications, and cataracts were sourced from independent genome-wide association study (GWAS) datasets. A two-step multivariable MR combined with mediation analysis was conducted to evaluate the indirect effects of serum metabolites in the causal pathway from T1D to cataracts. RESULTS: The MR analysis demonstrated a significant causal association between T1D and an increased risk of cataracts (OR = 1.01-1.05; p < 0.05). Further analysis showed that patients with T1D complications such as coma, ketoacidosis, nephropathy, and retinopathy exhibited a significantly higher risk of developing cataracts compared to those without complications. Sensitivity analyses upheld the robustness of these findings, with no evidence of heterogeneity or pleiotropy. Additionally, 102 serum metabolites were found to exhibit statistically significant mediation effects on cataract risk, with four (13-HODE + 9-HODE, 2-naphthol sulfate, docosadienoate (22:2n6), and X-12906) showing significant mediation effects. Specifically, 13-HODE + 9-HODE had a protective effect, while the other three metabolites were linked to an increased cataract risk. CONCLUSIONS: This study provides strong evidence of a causal link between T1D and cataracts, highlighting the mediating role of specific serum metabolites. These findings underscore the importance of early detection and management of cataracts in patients with T1D and suggest potential therapeutic targets for mitigating cataract risk. Further research should focus on replicating these findings in diverse populations and exploring the underlying metabolic pathways in greater detail.