预防湿性老年性黄斑变性的潜在药物靶点研究OA

AIM To identify potential drug targets for preventing wet senile macular degeneration(wet-SMD).METHODS A multi-level transcriptome-wide association study(TWAS)was performed to assess the effect of gene expression at the blood,brain and single-cell levels on the risk of wet-SMD.The overlap genes were further validated by Multimarker Analysis of Genomic Annotation(MAGMA)and strengthened by colocalization analyses.Protein-protein interaction network,enrichment,cell-cell communication,drug screening and molecular docking analysis were conducted to investigate the functional roles of candidate targets and potential drugs for preventing wet-SMD.RESULTS PLEKHA1 and RAPGEF6 were identified by multi-level TWAS,confirmed by MAGMA and strengthened by colocalization analysis.Cell-cell communication analysis indicated that signaling through TGFB1-(ACVR1B+TGFBR2),ANGPTL4-CDH5,MDK-NCL and VEGFB-VEGFR1 pathways may be implicated in the mechanism of PLEKHA1 on wet-SMD.VEGFB-VEGFR1 and MDK-SDC4 interactions could be key to understanding the role of RAPGEF6 in wet-SMD pathology.Drug screening and molecular docking analysis suggested that α-tocopherol and citric acid might be the potential drugs for preventing wet-SMD.CONCLUSION PLEKHA1 and RAPGEF6 are associated with wet-SMD risk,which might enhance our understanding of wet-SMD pathogenesis and highlight potential drug targets for prevention of wet-SMD.