Susceptibility and Protective Genes in Diabetic Retinopathy: A Comprehensive Single-Cell RNA Sequencing Analysis.

Abstract

Diabetes, an epidemic marked by increased blood glucose levels, is an endocrine disorder projected to impact 693 million individuals by 2045. The disease leads to significant morbidity and mortality primarily due to vascular complications, such as cardiovascular disease and diabetic kidney disease, imposing substantial economic burdens globally. Notably, type 2 diabetes (T2D) exhibits considerable heterogeneity in mechanisms and health outcomes. Recent advancements in clustering techniques have revealed clinically distinct subgroups of T2D, emphasizing the complexity of its complications influenced by both genetic and environmental factors. In our study, we utilized single-cell RNA sequencing (scRNA-seq) profiles from peripheral blood mononuclear cells of individuals with diabetes and diabetic retinopathy (DR) to elucidate the genetic underpinnings of this complication. We identified key genes associated with the susceptibility and severity of DR, establishing a diabetic retinal regulatory network. Notable findings include the role of Discoidin Domain Receptor 1 (DDR1) in promoting proinflammatory pathways, while genes such as TELO2, SNX30 and HLA-DRA appear to confer protective effects. Our investigation highlights the intricate balance between risk and protective factors in DR pathogenesis. Furthermore, molecular docking analyses identified potential therapeutic agents targeting these genes, suggesting new avenues for treatment. Overall, our results underscore the importance of understanding genetic influences on DR and propose a framework for future research and therapeutic strategies aimed at mitigating diabetic complications.