ObjectiveTo investigate the potential role of immune cells in retinal ischemia-reperfusion injury (RIRI)-associated diseases, employing Mendelian randomization (MR) and colocalization analysis. MethodsGenome-wide association study (GWAS) datasets of immune cells were obtained for conducting two-sample bidirectional MR analysis and colocalization analysis. A total of 731 immune cell phenotypes from the GWAS datasets were selected as exposure variables, and four RIRI-related diseases, namely diabetic retinopathy (DR), primary angle-closure glaucoma (PACG), retinal artery occlusion (RAO), and retinal vein occlusion (RVO), were chosen as outcome variables. The 731 immune cell phenotypes included seven cell types: B cells, classical dendritic cells, T cell maturation stages, monocytes, myeloid cells, TBNK cell group [T cells, B cells, and natural killer cells], and regulatory T cells. The inverse variance weighted (IVW) method was used to assess the causal relationship between immune cell phenotypes and RIRI-related diseases; colocalization analysis was performed to verify the possibility of shared causal variants between immune cell phenotypes and outcomes. ResultsThe IVW method analysis results showed that 117 were related to RIRI. After adjusting the false discovery rate (FDR) (PFDR＜0.05) and conducting reverse MR analysis, 19, 49, 37, 13, and 9 types of immune cell phenotypes were respectively associated with potential causal relationships with non-proliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), PACG, RAO, and RVO. Among them, in the monocyte group, CD64 on CD14+ CD16+ monocyte significantly increased the risk of NPDR occurrence [odds ratio (OR)=1.544, 95% confidence interval (CI) 1.184-2.014, P=0.011], and CX3CR1 on monocyte significantly decreased the risk of NPDR occurrence (OR=0.823, 95% CI 0.727-0.933, P=0.012); in the TBNK cell group, CD4+ CD8dim% T cells significantly increased the risk of PACG occurrence (OR=1.262, 95%CI 1.075-1.483, P=0.025), and CD8 on EM CD8+ T cells was a risk factor for PACG occurrence (OR=1.156, 95%CI 1.049-1.275, P=0.026). The colocalization analysis results showed that 32 types of immune cell phenotypes had significant common causal variant signals with outcome variables (posterior probability H4＞0.8), located at 14 gene loci. Five immune cell phenotypes related to B-cell activating factor receptors and PDR were jointly located at the CENPM and TNFRSF13C gene loci. the specific T cell subsets CD45RA-CD4+ T cells and cytotoxic T cell phenotype CD28+CD45RA-CD8dim T cells (a type of memory CD8dim T cell) were colocalized with PACG at the PTPRC gene. The CD33 and RVO on myeloid cell phenotype monocyte-like myeloid-derived suppressor cells are jointly located at the CD33 locus (rs3865444) of their encoding gene. ConclusionMR and colocalization analysis results reveal complex genetic causal relationships between multiple immune cell phenotypes and four RIRI-related diseases.
Objective To investigate the potential mechanism of cellular senescence-related mitochondrial autophagy genes in diabetic retinopathy (DR). MethodsThe DR gene datasets GSE53257 and GSE60436 from the GEO database and screened the differentially expressed genes (DEG) were downloaded. Cellular senescence-related genes and mitochondrial autophagy-related genes from the GeneCards database, and the intersection of the two to obtain the DR-related differentially expressed genes (CSRMRDEG) were collected. The obtained CSRMRDEG was subjected to Gene Ontology (GO) functional enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis, protein-protein interaction network (PPI) analysis, and hub gene identification using Maximal Clique Centrality (MCC), Degree, Maximum Neighborhood Component (MNC)、Edge Percolated Component (EPC) and Closeness algorithms. Gene Set Enrichment Analysis (GSEA) was conducted to obtain the enriched pathways of DEG, and ssGSEA immune infiltration analysis was performed to screen the correlation between immune cells and DR. The diagnostic efficacy of hub genes for DR was evaluated by drawing the receiver operating characteristic (ROC) curve and calculating the area under the curve (AUC). Meanwhile, the Wilcoxon rank sum test was used to compare the differences in the infiltration level of immune cells between the DR Group and the control group. Results23 DR-related CSRMRDEG were obtained. GO analysis showed that they were mainly enriched in the pathways of dicarboxylic acid, biosynthetic process of folate-containing compounds, tetrahydrofolate conversion, mitochondrial matrix, mitochondrial endomembrane, structural components of ribosomes, and glutamate transmembrane transporter protein activity. The results of KEGG pathway enrichment analysis showed that CSRMRDEG was highly enriched in pathways such as the folate carbon pool, biosynthesis of cofactors, and pyruvate metabolism. The PPI analysis results show that there are 16 related CSRMRDEG. Five algorithms (MCC, Degree, MNC, EPC, Closeness) obtained the nine Hub genes. The results of ROC curve analysis showed that the AUC of the expression levels of 9 hub genes for diagnosing DR ranged from 0.7-0.9. The ssGSEA results showed that there were statistically significant differences in Wilcoxon of central memory CD4+ T cells, macrophages, natural killer cells, and helper T cell 1 between the DR group and the control group (Z=−2.85, −2.23, −2.10, −2.52; P＜0.05). ConclusionMitochondrial autophagy genes related to cellular senescence are potential diagnostic targets for DR.