Causal roles of lipids and mediating proteins in diabetic retinopathy: insights from metabolomic and proteomic Mendelian randomization.

backgroundThis 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.

methodsWe 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.

resultsTriglycerides 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).

conclusionsThis 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.