VTE is a systemic disease. A study of more than 1 million cancer patients showed that the incidence of VTE increased by 28% between 1995 and 2003. In addition, among VTE patients, cancer patients can account for up to 20%, so it is crucial to study the mechanism of VTE. Mauracher LM et al studied the mechanism of cancer-related VTE and found that biomarkers formed by Neutrophil extracellular traps (NETs) are related to the occurrence of VTE in cancer patients, and can become a new pathogenic mechanism reflecting cancer-related VTE. At present, although a lot of work has been devoted to the study of VTE molecular mechanism, the related research is still in the exploratory stage. Therefore, the research on VTE related molecular mechanisms can not only re-understand the pathogenesis of VTE, but also provide new ideas for clinical treatment. Omics and bioinformatic algorithms, mostly network-oriented, are one of the most effective ways to capture new pathways of cardiovascular disease[21,22]. Based on this, the molecular level analysis of VTE was carried out by bioinformatics to provide new targets for the prevention and treatment of VTE.
The immune cell analysis of this study showed that monocytes and resting mast cells were significantly overexpressed in VTE, while regulatory T cells were significantly lower expressed. A study suggested that monocyte-related inflammatory mechanisms may be involved in the pathophysiological processes of VTE. Monocytes, platelet aggregation, and C-reactive protein are associated with VTE, which supports the conclusion that VTE is associated with inflammation. GO enrichment analysis found that DEGs are mainly involved in the composition of ribosomes in the cytoplasm. The occurrence of VTE is related to the ribosomes, cytochrome C oxidase activity, and the oxidoreductase activity on heme. It has been reported that the heme released by the large amount of erythrolysis in early thrombus is the main source of vascular endothelial cell oxidation, which can further lead to endothelial cell dysfunction and thrombosis[25,26]. Since heme is an inflammatory substance, the inflammatory process is increasingly recognized as an important mechanism for regulating thrombosis. In addition, heme can also promote the transformation of LDL into cytotoxic oxidation products. Elevated oxidized LDL is a known risk factor for cardiovascular and cerebrovascular diseases, and it is also a common independent risk factor for VTE. As can be seen, the oxidoreductase acting on heme plays an important role in VTE.
KEGG pathway enrichment analysis showed that DEGs are mainly involved in ribosomes, oxidative phosphorylation, Huntington's disease, Parkinson's disease, myocardial contraction and other processes. In addition, the 10 hub genes RPS29, RPL9, RPL27, RPS15A, RPS17, RPS27, RPS24, RPL30, RPL34 and RPL35 screened from DEGs all belong to the ribosomal protein family, and they are all highly expressed in VTE. Studies have shown that cardiovascular and cerebrovascular diseases are important risk factors for VTE, and ribosomes can be used as targets for cardiovascular diseases. Therefore, it can be speculated that there is a certain connection between them. In addition, scholars have found that ribosomes play an important role in the translation of platelet proteins, and platelets can promote the formation of NETs, which in turn promotes the formation of deep vein thrombosis. This conclusion supports our speculation. However, there is little direct evidence of ribosomal protein family genes associated with thrombosis.
Inflammation is one of the initial responses of the immune system to stimulus. Studies have found that immune dysfunction may be associated with the occurrence of VTE. Recently, scholars can use immunology to explain some "unprovoked" VTE cases. In order to further clarify the relationship between VTE and the immune system, we selected three immune differential genes S100A12, NR1D2 and CD3G from DEGs, which were significantly overexpressed in VTE. Calcium binding protein S100A12 is an immune molecule present on the mucosal surface, which is mainly secreted by neutrophils. In addition, an increase in the number of neutrophils can increase the risk of VTE events. A cross-sectional study of 550 hemodialysis patients showed that S100A12 protein levels were closely related to the prevalence of cardiovascular disease. Therefore, S100A12 can be considered as a biomarker for inflammatory diseases such as VTE. Studies have found that genetic defects of CD3G can lead to impaired expression of CD3 and TCR on the cell surface, so CD3G mutations are related to immune function defects. CD3G gene polymorphism may affect the occurrence of liver cancer. At present, most of the research on CD3G focuses on tumors, and there are few reports on vascular diseases and thrombosis. NR1D2, a nuclear hormone receptor gene, is associated with circadian rhythm, and circadian dysregulation widely affects Ras signaling pathways, T cell receptor signaling pathways, and then triggers various diseases such as tumors. NR1D2 is also an important regulator of vascular inflammation and is related to the occurrence of cardiovascular events. As a common complication of tumor, VTE may be closely related to immune genes CD3G and NR1D2.
Compared with previous studies, this article focuses on the genetics and immunology of VTE, and finds that ribosomal protein family genes and immune-related genes are closely related to VTE, which provides new ideas for further exploring the pathogenesis of VTE. Of course, this study also has some limitations. First, the chip data in this study is a single-center study with limitations in representativeness. Second, the molecular mechanism and therapeutic targets of VTE still need to be verified by a series of experiments.