RESUMEN
Purpose: Since age-related macular degeneration (AMD) is tightly associated with aging and cellular senescence, objective of this study was to investigate the association between plasma levels of senescence-related proteins (SRPs) and risk of AMD. Design: The whole study was based on two-sample Mendelian randomization (MR) analysis. Methods: For MR analysis, the primary approach for MR analysis was the inverse-variance weighted (IVW) method and the heterogeneity and pleiotropy of results were tested. The instrumental single-nucleotide polymorphisms (SNPs) associated with 110 SRPs were filtered and selected from a large genome-wide association study (GWAS) for plasma proteome involving 35,559 participants. The GWAS data of AMD was obtained from FinnGen consortium (6,157 AMD cases and 288,237 controls) and further validated by using data from UK Biobank consortium (3,553 AMD cases and 147,089 controls). Results: The MR results at both discovery and validation stages supported the causality (IVW-P < 0.00045) between plasma levels of 4 SRPs (C3b, CTNNB1, CCL1, and CCL3L1) and the risk of AMD and supported potential causality (IVW-P < 0.05) between other 10 SRPs and risk of AMD. No heterogeneity or pleiotropy in these results was detected. Conclusion: Our findings supported that high plasma levels of C3b, CTNNB1, CCL1, and CCL3L1 were associated with increased risk of AMD, thereby highlighting the role of systemic inflammation in AMD pathogenesis and providing the rationale for developing new preventative and therapeutic strategies.
RESUMEN
Purpose: To investigate the role of senescence-related cytokines (SRCs) in the pathophysiology of age-related macular degeneration (AMD). Design: The whole study is based on single-cell and bulk tissue transcriptomic analysis of the human neuroretinas with or without AMD. The transcriptomic data of human neuroretinas was obtained from Gene-Expression Omnibus (GEO) database. Methods: For single-cell transcriptomic analysis, the gene expression matrix goes through quality control (QC) filtering, being normalized, scaled and integrated for downstream analysis. The further analyses were performed using Seurat R package and CellChat R package. After cell type annotation, the expression of phenotype and functional markers of microglia was investigated and cell-cell communication analysis was performed. For bulk tissue transcriptomic analysis, GSE29801 dataset contains the transcriptomic data of human macular neuroretina (n = 118) from control group and AMD patients. The expression of SPP1 in control and AMD subtypes were compared by Student's t-test. In addition, the AMD macular neuroretina were classified into SPP1-low and SPP1-high groups according to the expression level of SPP1. The differentially expressed genes between these two groups were subsequently identified and the pathway enrichment analysis for these genes was further conducted. Results: Secreted phosphoprotein 1, as an SRC, was revealed to be highly expressed in microglia of AMD neuroretina and the SPP1-receptor signaling was highly activated in AMD neuroretina. In addition, SPP1 signaling was associated with the pro-inflammatory phenotype and phagocytic state of microglia. SPP1 expression was elevated in macular neuroretina with late dry and wet AMD and the inflammatory pathways were found to be activated in SPP1-high AMD macular neuroretina. Conclusion: Our findings indicated that SPP1 and microglial activation might play an important role in the pathophysiology of AMD. Therefore, SPP1 might serve as a potential therapeutic target for AMD. More in vitro and in vivo studies are required to confirm the results and the therapeutic effect of SPP1-targeting strategy.