Genome-wide Mendelian randomization study identifies therapeutic targets for diabetic microangiopathy
Xiongyi Yang1, Qian Liu1, Qian Ma2
1Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
Aims:
This study aims to identify potential therapeutic targets for diabetic microangiopathy by integrating genome-wide association studies (GWAS) and Mendelian randomization (MR) analyses.
Methods:
A comprehensive analysis of GWAS datasets on diabetic microangiopathy was conducted by using two-sample MR to determine the causal effects of blood-expressed druggable genes at both the transcriptional and protein levels. Co-localization analysis was conducted to validate gene-trait associations, while phenome-wide association studies (PheWAS) explored broader phenotypic implications. Additionally, protein-protein interaction (PPI) networks were constructed to elucidate gene interactions and molecular docking was conducted to determine therapeutic druggability.
Results:
Nine candidate therapeutic targets (PSORS1C3, HLA-C, RAMP1, CTSG, SREBF1, BTN3A2, PPA1, PRKD2, and PPIG) were identified, with co-localization analysis confirming their involvement in diabetic microangiopathy. Among them, HLA-C exhibited associations with additional traits, suggesting the specificity of the remaining targets. Functional enrichment analysis indicated a predominant involvement of immune-related pathways, underscoring their relevance to the pathogenesis of diabetic microangiopathy. Furthermore, molecular docking studies revealed strong binding affinities.
Conclusions:
This study provides compelling genetic evidence supporting the role of immune-related druggable genes in diabetic microangiopathy and identifies novel therapeutic targets for intervention.
