Endophenotype Network Models: Common Core of Complex Diseases

S. D. Ghiassian, J. Menche, D. I. Chasman, F. Giulianini, R. Wang, P.Ricchiuto, M. Aikawa, H. Iwata, C. Muller, T. Zeller, A. Sharma, P. Wild, K. Lackner, S. Singh, P. M. Ridker, S. Blankenberg, A.-L. Barabasi, J. Loscalzo.
Scientific Reports
6: 27414, 1-13 (2016).
June 9, 2016

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.

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