The module triad: a novel network biology approach to utilize patients’ multi-omics data for target discovery in ulcerative colitis

Abstract

Tumor necrosis factor-alpha inhibitors (TNFi) have been a standard treatment in ulcerative colitis (UC) for nearly 20 years. However, insufficient response rate to TNFi therapies along with concerns around their immunogenicity and inconvenience of drug delivery through injections calls for development of UC drugs targeting alternative proteins. Here, we propose a multi-omic network biology method for prioritization of protein targets for UC treatment. Our method identifies network modules on the Human Interactome—a network of protein-protein interactions in human cells—consisting of genes contributing to the predisposition to UC (Genotype module), genes whose expression needs to be modulated to achieve low disease activity (Response module), and proteins whose perturbation alters expression of the Response module genes to a healthy state (Treatment module). Targets are prioritized based on their topological relevance to the Genotype module and functional similarity to the Treatment module. We demonstrate utility of our method in UC and other complex diseases by efficiently recovering the protein targets associated with compounds in clinical trials and on the market . The proposed method may help to reduce cost and time of drug development by offering a computational screening tool for identification of novel and repurposing therapeutic opportunities in UC and other complex diseases.