Abstract
BACKGROUND: This study explores the causal relationships between five major lipids, 249 circulating metabolites, and four diabetic retinopathy (DR) outcomes: overall DR, background DR, severe background DR, and proliferative DR (PDR). We aim to identify plasma proteins that mediate these causal effects, offering insights into potential therapeutic targets. METHODS: We conducted metabolome-wide Mendelian randomization (MR) analyses to assess associations between major lipids, metabolites, and DR outcomes. Multivariable MR (MVMR) and proteome-wide mediated MR (two-step MR) analyses were performed to ensure robust evaluation and identify mediating plasma proteins. RESULTS: Triglycerides were identified as a significant risk factor for DR, mediated by proteins like Dickkopf-3 (DKK3), ST6 N-acetylglucosamine transferase 6 (ST4S6), and Neogenin (NEO1). For background DR, HDL-C, specific VLDL particles, and LDL triglycerides were protective, mediated by proteins like chloride intracellular channel 5 (CLIC5), basal cell adhesion molecule (BCAM), and Ribophorin I (RPN1). Additionally, polyunsaturated fatty acids (PUFAs) and total choline were protective against PDR, mediated by Radical Fringe Gene (RFNG). CONCLUSIONS: This study identifies specific plasma proteins that mediate the effects of lipids and metabolites on DR, establishing a direct molecular link between these biomarkers and disease progression. These findings enhance our understanding of the pathophysiological mechanisms underlying DR and highlight potential targets for therapeutic intervention.