The structure of the cytokine gene network in uterine fibroids

Abstract

The structure of 166416 gene chains of various dimensions consisting of polylocus combinations of 12 polymorphic positions which forming cytokine gene network which associated with the development of uterine fibroids was studied. The structural and functional organization of the cytokine gene network, which associated with uterine fibroids resistance, was also studied for comparison. Computer modeling of network interactions of cytokine genotypes of various nature involved in the regulation of inflammation, angiogenesis, destruction and remodeling of connective tissue involved in the pathogenesis of polygenic diseases, including uterine fibroids, was performed using the Cytoscape bioinformatics platform. Analysis of the topology of this gene network allowed us to identify the main genes and the main intergenic interactions that make the greatest contribution to the development of uterine fibroids. The main genes for the development of uterine fibroids can be 3 polymorphisms: IL1B-31TC, VEGF+936CT and IL10-592CA. These genes form the main nodes in the gene network because they have the most interactions with other genes. The main intergenic interactions are the following paired combinations of polymorphisms: [IL1B-31TC : IL10-592CA] (13,5%), [TNF-238GG : IL1B-31TC] (12,0%), [IL1B-31TC : IL10-1082AG] (10,5%), [TNF-863CC : IL1B-31TC] (9,7%), [TNF-238GG : VEGF+936CT] (9,0%), since they account for 55% of all major interactions in the gene network associated with uterine fibroids development. These composite gene patterns can determine the predisposition to the uterine fibroids development, affecting the intensity of immune inflammation processes and the activity of neoangiogenesis in the myometrium. On the other hand, a characteristic feature of the structural and functional organization of the cytokine gene network, which associated with uterine fibroids resistance, is its ability to self-regulate the levels of promoter activity of angiogenesis and inflammation regulator genes due to regulatory circuits with a common hub in the form of the homozygous VEGF+936CC genotype. The most frequent intergenic interactions are associated with this vertex: [TNF-238 GG : VEGF+936 CC] (13.2%), [TNF-863 CC : VEGF+936 CC] (13.2%), [IL4-590 CC :VEGF+936 CC] (7.9%), and [VEGF+936 CC : MMP9-1562 CC] (7.9%). This gene network ensures the balanced flow of angiogenesis processes, the functioning of the extracellular matrix and the processes of inflammation in the myometrium, which prevents the development of uterine fibroids.