Proteome atlas for mechanistic discovery and risk prediction of diabetic retinopathy
Proteomics offers an unprecedented opportunity to characterize and predict diabetic retinopathy (DR) with minimal invasiveness. Here we examine this in 10,873 individuals with (pre)diabetes from two ethnically distinct cohorts. By simultaneous profiling of ~3000 proteins, we identify 668 associations with mechanistically plausible directionality that constitute a comprehensive DR proteomic landscape with linkages to retinal tomographic structure and genetic predisposition, pointing to established and novel biological pathways conferring DR risk. Integrating DR proteomic profile markedly improves predictive performance beyond clinical and genetic predictors, with plexin B2, growth differentiation factor 15, and renin emerging as top proteins validated across cohorts and linked to retinal microvascular degeneration in Guangzhou Diabetic Eye Study (GDES) based on SS-OCTA. A parsimonious panel of these three proteins alone achieves comparable performance in predicting DR development and progression, while renin is confirmed as a causal promoter through genetic analyses. Our findings highlight the potential of large-scale proteomics in elucidating DR pathogenesis and advancing biomarker discovery, with broad implications for early detection and intervention.
Authors
- Wenyong Huang (ORCID: https://orcid.org/0000-0003-3167-0851)
- Zhuoting Zhu (ORCID: https://orcid.org/0000-0002-9897-1192)
- Mingguang He (ORCID: https://orcid.org/0000-0002-6912-2810)
- Li Du (ORCID: https://orcid.org/0000-0001-8864-6380)
- Huangdong Li (ORCID: https://orcid.org/0000-0003-3017-9569)
- Ruilin Xiong (ORCID: https://orcid.org/0000-0002-8364-7859)
- Ching‐Yu Cheng (ORCID: https://orcid.org/0000-0003-0655-885X)
- Shaopeng Yang (ORCID: https://orcid.org/0000-0002-4330-7841)
- Nathan Congdon (ORCID: https://orcid.org/0000-0001-9866-3416)
- Xianwen Shang (ORCID: https://orcid.org/0000-0001-6143-9349)
- Jost Bruno Jonas (ORCID: https://orcid.org/0000-0003-2972-5227)
- Yih Chung Tham (ORCID: https://orcid.org/0000-0002-6752-797X)
- Shaoying Tan (ORCID: https://orcid.org/0000-0001-9997-7396)
- Zhiyong Zhong (ORCID: https://orcid.org/0000-0003-2079-3186)
- Wei Wang (ORCID: https://orcid.org/0000-0002-5273-3332)
- Yanping Chen (ORCID: https://orcid.org/0000-0002-5804-2452)
- Lei Zhang (ORCID: https://orcid.org/0000-0003-2343-084X)
- Shida Chen (ORCID: https://orcid.org/0000-0003-0907-0614)
- Ziyu Zhu (ORCID: https://orcid.org/0009-0005-0268-9563)
- Chang Shu He (ORCID: https://orcid.org/0009-0003-8464-2392)
- Zhuoyao Xin
Institutions
- Queen's University Belfast (GB)
- Kennedy Krieger Institute (US)
- Hong Kong Polytechnic University (HK)
- Johns Hopkins University (US)
- Sun Yat-sen University (CN)
- National University of Singapore (SG)
- Institut Français (FR)
- Singapore National Eye Center (SG)
- Shanghai Eye Disease Prevention & Treatment Center (CN)
- Melbourne Sexual Health Centre (AU)
- Centre for Eye Research Australia (AU)
- Singapore Eye Research Institute (SG)
- Fondation de Rothschild (FR)
- Hainan Eye Hospital (CN)
- Second Affiliated Hospital of Nanjing Medical University (CN)
- Alfred Health (AU)
- Monash University (AU)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-31
- DOI
- https://doi.org/10.1038/s41467-025-64634-1
- Citations
- 1
- Primary Topic
- Retinal Diseases and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 1.71
Funders
- National Natural Science Foundation of China
- Hong Kong Polytechnic University
- Health and Medical Research Fund