Analysis of type 2 diabetes mellitus-related genes by constructing the pathway-based weighted network.

Abstract

Complex network is an effective approach to studying complex diseases, and provides another perspective for understanding their pathological mechanisms by illustrating the interactions between various factors of diseases. Type 2 diabetes mellitus (T2DM) is a complex polygenic metabolic disease involving genetic and environmental factors. By combining the complex network approach with biological data, this study constructs a pathway-based weighted network model of T2DM-related genes to explore the interrelationships between genes, here a weight is assigned to each edge in terms of the number of the same pathways in which the two nodes (genes) connected to the edge are involved. The edge weights can reflect differences in the strength of connections (interactions) between nodes (genes), which intuitively reflect the extent of biological correlations between genes and contribute to the importance of the nodes. Analysis of statistical and topological characteristics shows that the edge weights are correlated to the network topology, and the edge weight distribution decays as a power-law. The disparity of the weights indicates that the edge weight distribution for the nodes with the same degree is of approximately equal weights; and most edges with the higher weights tend to connect with the higher degree nodes. To determine the key hub genes of the weighted network, an integrated ranking index is used to comprehensively reflect the contribution of the three indices (strength, degree and number of pathways) of nodes; by taking the threshold of integrated ranking index greater than 0.56, 12 key hub genes are identified: MAPK1, PIK3CD, PIK3CA, PIK3R1, AKT2, AKT1, KRAS, TNF, MAPK8, PRKCA, IL6 and MTOR. These genes should play an important role in the occurrence and development of T2DM, and can be regarded as potential therapeutic targets for further biological and medical research on their functions in T2DM. It can be expected that combining complex network approach with other data analysis techniques can provide more clues for exploring the pathogenesis and treatment of T2DM and other complex diseases in the future.