Network analysis of atherosclerotic genes elucidates druggable targets

Atherosclerosis is one of the major causes of cardiovascular disease. It is characterized by the accumulation of atherosclerotic plaque in arteries under the influence of inflammatory responses, proliferation of smooth muscle cell, accumulation of modified low density lipoprotein. The pathophysiology of atherosclerosis involves the interplay of a number of genes and metabolic pathways. In traditional translation method, only a limited number of genes and pathways can be studied at once. However, the new paradigm of network medicine can be explored to study the interaction of a large array of genes and their functional partners and their connections with the concerned disease pathogenesis. Thus, in our study we employed a branch of network medicine, gene network analysis as a tool to identify the most crucial genes and the miRNAs that regulate these genes at the post transcriptional level responsible for pathogenesis of atherosclerosis.

From NCBI database 988 atherosclerotic genes were retrieved. The protein-protein interaction using STRING database resulted in 22,693 PPI interactions among 872 nodes (genes) at different confidence score. The cluster analysis of the 872 genes using MCODE, a plug-in of Cytoscape software revealed a total of 18 clusters, the topological parameter and gene ontology analysis facilitated in the selection of four influential genes viz., AGT, LPL, ITGB2, IRS1 from cluster 3. Further, the miRNAs (miR-26, miR-27, and miR-29 families) targeting these genes were obtained by employing MIENTURNET webtool.

Gene network analysis assisted in filtering out the 4 probable influential genes and 3 miRNA families in the pathogenesis of atherosclerosis. These genes, miRNAs can be targeted to restrict the occurrence of atherosclerosis. Given the importance of atherosclerosis, any approach in the understanding the genes involved in its pathogenesis can substantially enhance the health care system.