Presently, there is a growing body of evidence supporting the correlation between DR and AMD. This correlation highlights the need for a comprehensive understanding of their intricate mechanisms in order to develop improved diagnostic and therapeutic strategies for individuals affected by both DR and AMD. Although previous studies have suggested a genetic correlation between DR and AMD, the shared pathogenic pathway between the two conditions has not been fully elucidated. Therefore, the aim of the present study is to investigate and uncover the underlying mechanisms connecting DR and AMD8,11. This paragraph discusses the relationship between DM and AMD. It highlights several key points. First, DM can lead to the accumulation of advanced glycation end products in various tissues, including the retinal pigment epithelial cell layers and photoreceptors. This accumulation can cause damage to the retinal microvasculature, which is linked to the development of AMD. Second, hyperglycemia-induced oxidative stress is an important pathway in diabetes-related microvascular complications. This oxidative stress can contribute to premature aging in retinal pigment epithelium cells, thereby directly contributing to the development of AMD. Third, vascular endothelial growth factor (VEGF) is a key factor in both DR and AMD. Therefore, anti-VEGF therapy can be beneficial for the treatment of both conditions. Fourth, inflammatory mediators such as ICAM-1, MCP-1, IL-1b, IL-8, and TNF-a are involved in both DR and AMD. The onset of DR can lead to the disruption of the blood-retinal barrier, resulting in the release of these inflammatory mediators into DR patients. This release may potentially trigger the development of AMD8,10,12,13.
In this study, bioinformatic analyses were conducted using the gene expression profiles of the GSE160306 and GSE29801 datasets. The transcription levels of DR and AMD patients were found to have significant differences. GO and KEGG analysis based on these differences identified 61 significantly differentially expressed DEGs genes. These genes were found to be enriched in the neuroactive ligand-receptor interaction pathway, which plays a crucial role in the pathogenesis of DR and AMD. The neuroactive ligand-receptor interaction pathway consists of plasma membrane receptors that facilitate the movement of neuroactive ligands from outside the cell into the cell by binding to them. Previous studies have demonstrated the importance of this pathway in neurotransmitter-mediated diseases such as Parkinson's disease, diabetic encephalopathy, and certain lung cancers.14–16. In their study, Ding et al. discovered that the neuroactive ligand-receptor interaction pathway was highly enriched in human plasma samples, specifically in DR17. Previous research has highlighted the significance of this pathway in AMDRPE/choroid, with 30 genes, including the C5 gene, being potentially associated with AMD.18. However, there is a lack of studies investigating the relationship between DR and AMD in human retinal tissues and the neuroactive ligand-receptor interaction pathway. Thus, further research is needed to explore and confirm the specific mechanism. Our study, for the first time, identified five HUB genes (C5, KRAS, FSTL1, KCNV2, PILRB) through our research
Research studies have demonstrated a connection between AMD and DR with immune responses. The production of proinflammatory substances, particularly C5, plays a crucial role in advancing the development of AMD. Furthermore, C5a binds to receptors on retinal cells, triggering the production of inflammatory and angiogenic factors. Additionally, the interaction between C5aR and C5a in Müller cells results in the release of IL-6 and VEGF, which contribute to the pathology of DR19,20. Several studies have demonstrated that C5 levels are increased in human plasma and vitreous samples in cases of DR and AMD, respectively21–23. However, there has been no investigation into the levels of C5 in retinal tissues of patients with both DR and AMD. Therefore, we propose that C5 could serve as a significant marker for diagnosing patients with DR combined with AMD.
As a common member of the RAS family, somatic mutations of H-RAS, K-RAS, or N-RAS are frequently observed in the development of human tumors. Among these mutations, KRAS mutations are particularly prevalent in various cancers such as pancreatic ductal carcinoma (PDAC), rectal cancer, and lung cancer. KRAS plays a crucial role in signaling, regulating important cellular processes including cell proliferation, differentiation, growth, metabolism, and migration24,25. Previous studies have demonstrated that mutated K-ras oncogenes can stimulate the expression of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF)26. Furthermore, HRAS has also been found to be associated with DR.
FSTL1 is a glycoprotein induced by TGF-β. It is involved in cell proliferation, differentiation, and migration, and has been found to play a role in cardiovascular system, tumor, and other diseases. However, there have been limited studies on its role in ophthalmology27–29. Liang et al. conducted an analysis of the differential gene expression between AMD retinal tissue and normal retinal tissue. They observed that the expression of FSTL1 was higher in AMD compared to the normal control group. Niu et al. also investigated the potential involvement of FSTL1 in the pathogenesis of PDR by analyzing vitreous fluid and proliferative membrane samples from PDR patients30,31. These findings align with our results. Notably, there is a lack of studies examining FSTL1 in patients with both DR and AMD.
The diagnostic value of the five genes in both DR and AMD diseases was assessed using ROC curve analysis. However, there is currently no literature available that discusses the role of these five genes in either DR or AMD. Therefore, our study is the first to investigate the diagnostic value of these genes and their potential critical role in the pathogenesis of DR-AMD disease.
In this study, we have identified several HUB genes that show potential diagnostic performance for both DR and AMD through bioinformatics analysis. These findings offer promising prospects for diagnosis and treatment of these diseases. However, it is important to note that our study has certain limitations. The lack of existing research literature directly related to these genes necessitates the collection of more clinical samples for further experiments and functional analysis. This will enable a better understanding of the function, regulation, and interaction of these diagnostic genes in DR and AMD. Therefore, it is crucial to validate our results through in vitro and in vivo experiments as well as clinical practice.