TY - JOUR
T1 - Endophenotype Network Models
T2 - Common Core of Complex Diseases
AU - Ghiassian, Susan Dina
AU - Menche, Jörg
AU - Chasman, Daniel I.
AU - Giulianini, Franco
AU - Wang, Ruisheng
AU - Ricchiuto, Piero
AU - Aikawa, Masanori
AU - Iwata, Hiroshi
AU - Müller, Christian
AU - Zeller, Tania
AU - Sharma, Amitabh
AU - Wild, Philipp
AU - Lackner, Karl
AU - Singh, Sasha
AU - Ridker, Paul M.
AU - Blankenberg, Stefan
AU - Barabási, Albert László
AU - Loscalzo, Joseph
PY - 2016/6/9
Y1 - 2016/6/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84974528500&partnerID=8YFLogxK
U2 - 10.1038/srep27414
DO - 10.1038/srep27414
M3 - Article
C2 - 27278246
AN - SCOPUS:84974528500
SN - 2045-2322
VL - 6
JO - Scientific Reports
JF - Scientific Reports
M1 - 27414
ER -