Endophenotype Network Models: Common Core of Complex Diseases.

Susan Dina Ghiassian,Daniel I Chasman,Jörg Menche,Piero Ricchiuto,Franco Giulianini,Joseph Loscalzo,Karl Lackner,Amitabh Sharma,Christian Müller,Albert-László Barabási,Stefan Blankenberg,Sasha Singh,Hiroshi Iwata,Ruisheng Wang,Masanori Aikawa,Tania Zeller,Philipp Wild,Paul M Ridker

doi:10.1038/srep27414

Abstract

Historically, human diseases have been differentiated and categorized based on the organ system in which they primarily manifest. Recently, an alternative view is emerging that emphasizes that different diseases often have common underlying mechanisms and shared intermediate pathophenotypes, or endo(pheno)types. Within this framework, a specific disease’s expression is a consequence of the interplay between the relevant endophenotypes and their local, organ-based environment. Important examples of such endophenotypes are inflammation, fibrosis, and thrombosis and their essential roles in many developing diseases. In this study, we construct endophenotype network models and explore their relation to different diseases in general and to cardiovascular diseases in particular. We identify the local neighborhoods (module) within the interconnected map of molecular components, i.e., the subnetworks of the human interactome that represent the inflammasome, thrombosome, and fibrosome. We find that these neighborhoods are highly overlapping and significantly enriched with disease-associated genes. In particular they are also enriched with differentially expressed genes linked to cardiovascular disease (risk). Finally, using proteomic data, we explore how macrophage activation contributes to our understanding of inflammatory processes and responses. The results of our analysis show that inflammatory responses initiate from within the cross-talk of the three identified endophenotypic modules.

Highlights

Fibrosis in particular aiming to identify those molecular subnetworks or mediators that are common to all, as well as those that are distinctive for each
In order to obtain genes with high-confidence association, we used two filtering criteria: (a) genes whose association has been reported in at least two publications; and (b) genes that are expressed in tissues related to cardiovascular diseases
We observed that the three detected endophenotype modules are highly enriched with known disease genes, in general, and, with differentially expressed genes associated with cardiovascular risk factors

Summary

Introduction

Fibrosis in particular aiming to identify those molecular subnetworks or mediators that are common to all, as well as those that are distinctive for each. In this way, we can define the determinants of the interplay among these common endophenotypes, as well as the determinants of heightened or deficient responses in them. Several molecules and cell types play a crucial role in these processes and exert their function through a network of interactions. In this study we explore (a) network models of inflammation, thrombosis, and fibrosis; (b) their biological and topological crosstalk; and (c) the role of macrophages as central cellular mediators of these endophenotypes

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Results

Conclusion