HDGF as a Novel Serological Marker for Proliferative Diabetic Retinopathy: A Mendelian Randomization and Cross-Sectional Study

Purpose: To identify novel serum biomarkers to improve the diagnosis of proliferative diabetic retinopathy (PDR) and to assist the development of advanced treatment strategies. Methods: A Mendelian randomization (MR) analysis was conducted using a Genome-Wide Association Studies database to assess the causal relationship between serum HDGF levels and three retinopathy phenotypes: any diabetic retinopathy (DR), non-proliferative DR (NPDR), and PDR. A total of 65 diabetic patients were recruited including diabetic patients without DR (NDR), those with NPDR, and those with PDR, as well as 22 non-diabetic healthy controls (CON). Serum HDGF concentrations across all groups were quantified via a double-antibody sandwich enzyme-linked immunosorbent assay (ELISA). Results: The MR analysis revealed a significant positive causal association between the serum HDGF levels and PDR (odds ratio [OR] = 1.083; 95% confidence interval [CI], 1.007-1.163; P = 0.029). Furthermore, ELISA results revealed a progressive increase in serum HDGF levels, with the lowest concentrations observed in the CON group, followed by the NDR, NPDR, and PDR groups (highest levels). Significant differences were observed in selected pairwise comparisons, particularly between PDR and non-PDR groups. Conclusions: Our study establishes a positive causal relationship between serum HDGF levels and PDR. Furthermore, serum HDGF levels exhibit a progressive upward trend in DR patients, with levels increasing with disease severity. These results suggest HDGF as a potential biomarker for PDR. Translational Relevance: This study reveals a positive causal relationship between serum HDGF levels and PDR, providing potential therapeutic targets for disease prevention and treatment.