This study aims to elucidate the pathogenic mechanisms of Diabetic Retinopathy (DR) by integrating genomics, environmental exposures, and proteomics data, focusing on the interplay between genetic susceptibility, environmental factors, and dynamic proteomic changes. The scientific rationale is based on key observations: while diabetes is a prerequisite for DR, only 35-50% of diabetic patients develop DR, with significant variability in disease progression, suggesting critical roles of genetic and environmental modifiers. Genome-wide association studies (GWAS) have identified DR-associated loci (e.g., VEGFA, APOE), but these explain only part of the genetic risk. Epidemiological evidence also links environmental factors, such as glucose fluctuations and air pollution, to DR risk, yet their molecular mechanisms remain unclear. The proteome, as the ultimate effector of gene-environment interactions, may bridge this gap. For example, hyperglycemia may induce VEGF expression by promoting AGE-RAGE binding, while genetic variants may modulate this process.
This study addresses two key questions: First, do specific genetic variants exhibit synergistic effects on DR risk under certain environmental exposures, mediated through protein changes? Second, can a gene-protein-environment interaction model outperform traditional risk predictors? By integrating multi-omics data, this research aims to reveal DR’s molecular mechanisms and improve risk prediction and intervention strategies.
