Network Modules As Molecular Disease Definitions for Mechanism-Based Endotyping Anddrug Repurposing

We hardly understand any disease mechanistically and low precision drug interventions are the norm in the clinics [1,2].Current disease definitions are also organ-and symptom-based which runs the risk that different mechanisms that cause a similar symptom are subsumed under one umbrella term.They are thus converted into one common and complex disease entity, which is impossible to untangle based on the current diagnostic tools, leading to a longlasting classification of chronic diseases either based on symptoms or body location.The current treatment options for complex diseases are thus chronic interventions which are neither curative nor precise.Recent efforts have been made to redefine diseases by moving from symptom and organ to mechanism and cause [3].The ultimate aim is to endotype patients and reach precision medicine.Complex diseases, contrary to rare monogenic diseases, are not caused by a single gene or protein, but several affected elements within a diseased network, a disease module.We have previously identified a disease mechanism, involving genes related to reactive oxygen species (ROS) formation and cGMP signalling (ROCG).This disease mechanism or disease module is causal for a heterogeneous diseasome cluster of metabolic-cerebro-cardiovascular disease phenotypes [4].Hypertension and heart failure have been validated within the ROCG endotype in biobanked patient samples (1 out of 5 and 1 out of 3 patients respectively) [5].Stratifying patients according to both phenotype and endotype will enable high precision therapeutic interventions resulting in low number needed to treat.These data show that even for supposedly complex diseases, endotyping for precision medicine, and mechanistic disease re-definition is possible.