Prioritization of genes involved in endothelial cell apoptosis by their implication in lymphedema using an analysis of associative gene networks with ANDSystem

Abstract

BackgroundCurrently, more than 150 million people worldwide suffer from lymphedema. It is a chronic progressive disease characterized by high-protein edema of various parts of the body due to defects in lymphatic drainage. Molecular-genetic mechanisms of the disease are still poorly understood. Beginning of a clinical manifestation of primary lymphedema in middle age and the development of secondary lymphedema after treatment of breast cancer can be genetically determined. Disruption of endothelial cell apoptosis can be considered as one of the factors contributing to the development of lymphedema. However, a study of the relationship between genes associated with lymphedema and genes involved in endothelial apoptosis, in the associative gene network was not previously conducted.MethodsIn the current work, we used well-known methods (ToppGene and Endeavour), as well as methods previously developed by us, to prioritize genes involved in endothelial apoptosis and to find potential participants of molecular-genetic mechanisms of lymphedema among them. Original methods of prioritization took into account the overrepresented Gene Ontology biological processes, the centrality of vertices in the associative gene network, describing the interactions of endothelial apoptosis genes with genes associated with lymphedema, and the association of the analyzed genes with diseases that are comorbid to lymphedema.ResultsAn assessment of the quality of prioritization was performed using criteria, which involved an analysis of the enrichment of the top-most priority genes by genes, which are known to have simultaneous interactions with lymphedema and endothelial cell apoptosis, as well as by genes differentially expressed in murine model of lymphedema. In particular, among genes involved in endothelial apoptosis, KDR, TNF, TEK, BMPR2, SERPINE1, IL10, CD40LG, CCL2, FASLG and ABL1 had the highest priority. The identified priority genes can be considered as candidates for genotyping in the studies involving the search for associations with lymphedema.ConclusionsAnalysis of interactions of these genes in the associative gene network of lymphedema can improve understanding of mechanisms of interaction between endothelial apoptosis and lymphangiogenesis, and shed light on the role of disturbance of these processes in the development of edema, chronic inflammation and connective tissue transformation during the progression of the disease.Electronic supplementary materialThe online version of this article (10.1186/s12920-019-0492-9) contains supplementary material, which is available to authorized users.

Bioinformatic Reconstruction and Analysis of Gene Networks Related to Glucose Variability in Diabetes and Its Complications

“…It utilizes text mining, an automatic knowledge extraction from the texts of scientific publications. Previously, the ANDSystem was used to identify candidate genes associated with comorbidity of asthma and tuberculosis [ 119 ], preeclampsia, diabetes and obesity [ 120 ], primary open-angle glaucoma [ 121 ], asthma and hypertension [ 122 ], and lymphedema [ 123 ].…”

ANDDigest: a new web-based module of ANDSystem for the search of knowledge in the scientific literature

“…The ANDSystem tool [49][50][51][52], previously developed by us, is another instance of systems that carry out a full cycle of engineering and management of knowledge. The ANDSystem tool is based on unique, specialized ontology [50], which, in many respects, outperforms the existing analogues by the description of a subject area.…”

Effect of apigenin on whole transcriptome profile of TNFα‑activated MDA‑MB‑468 triple negative breast cancer cells

“…What is evidently a critical situation is that these inflammatory proteins, in particular, the CCL2 and IL-6 are brought about by the actual cancer treatments themselves (e.g., radiotherapy (16) chemotherapy (8), which in turn are then associated with tumor recurrence (17) and chemo-resistance (18,19), Inflammatory events in general, whether it be from other parts of the body such as the liver (9,20) adipose tissue in obesity or arising from viral origin tend to elevate TNF-a, IL -6 and CCL2 then becoming risk factors for the development of diverse cancers (21) aggressive tumors with advanced stage tumor grade and greater rates of mortality (22,23). Meanwhile, it is believed that drugs or natural compounds that can attenuate CCL2 and IL-6 would slow the aggressive nature of advanced cancers (24)(25)(26) to the inclusion of triple negative breast cancer (TNBC) and hormone positive breast cancers (27,28). It is believed that utilizing synthetic or natural small molecules as CCR2 inhibitors (CCR2i) can increase overall survival odds (29,30).…”