Exploration of potential novel drug targets for diabetic retinopathy by plasma proteome screening

The aim of this study is to identify novel potential drug targets for diabetic retinopathy (DR). A bidirectional two-sample Mendelian randomization (MR) analysis was performed using protein quantitative trait loci (pQTL) of 734 plasma proteins as the exposures and clinically diagnosed DR as the outcome. Genetic instruments for 734 plasma proteins were obtained from recently published genome-wide association studies (GWAS), and external plasma proteome data was retrieved from the Icelandic Decoding Genetics Study and UK Biobank Pharma Proteomics Project. Summary-level data of GWAS for DR were obtained from the Finngen Consortium, comprising 14,584 cases and 202,082 population controls. Steiger filtering, Bayesian co-localization, and phenotype scanning were used to further verify the causal relationships calculated by MR. Three significant (p < 6.81 × 10^-5) plasma protein-DR pairs were identified during the primary MR analysis, including CFH (OR = 0.8; 95% CI 0.75-0.86; p = 1.29 × 10^-9), B3GNT8 (OR = 1.09; 95% CI 1.05-1.12; p = 5.9 × 10^-6) and CFHR4 (OR = 1.11; 95% CI 1.06-1.16; p = 1.95 × 10^-6). None of the three proteins showed reverse causation. According to Bayesian colocalization analysis, CFH (coloc.abf-PPH4 = 0.534) and B3GNT8 (coloc.abf-PPH4 = 0.638) in plasma shared the same variant with DR. All three identified proteins were validated in external replication cohorts. Our research shows a cause-and-effect connection between genetically determined levels of CFH, B3GNT8 and CFHR4 plasma proteins and DR. The discovery implies that these proteins hold potential as drug target in the process of developing drugs to treat DR.