Endophenotype Network Models: Common Core of Complex Diseases.
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.
Center for Complex Networks Research and Department of Physics, Northeastern University, Boston, MA, USA.|Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Susan Dina
SD
Ghiassian
Center for Complex Networks Research and Department of Physics, Northeastern University, Boston, MA, USA.|Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Boston, MA, USA.|Department of Theoretical Physics, Budapest University of Technology and Economics, Budapest, Hungary.
Jörg
J
Menche
Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Daniel I
DI
Chasman
Informaton Systems, Brigham and Women's Hospital, Boston, MA, USA.
Franco
F
Giulianini
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Ruisheng
R
Wang
Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Piero
P
Ricchiuto
Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Masanori
M
Aikawa
Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Hiroshi
H
Iwata
University Heart Center Hamburg, Clinic for General and Interventional Cardiology, Hamburg, Germany.|German Center for Cardiovascular Research (DZHK), Partner site Hamburg/Lübeck/Kiel, Hamburg, Germany.
Christian
C
Müller
University Heart Center Hamburg, Clinic for General and Interventional Cardiology, Hamburg, Germany.|German Center for Cardiovascular Research (DZHK), Partner site Hamburg/Lübeck/Kiel, Hamburg, Germany.
Tania
T
Zeller
Center for Complex Networks Research and Department of Physics, Northeastern University, Boston, MA, USA.|Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Boston, MA, USA.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Amitabh
A
Sharma
German Center for Cardiovascular Research (DZHK), Partner site Hamburg/Lübeck/Kiel, Hamburg, Germany.|Preventive Cardiology and Preventive Medicine, Dept. of Medicine 2, University Medical Center Mainz, Mainz, Germany.|Clinical Epidemiology, Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany.
Philipp
P
Wild
German Center for Cardiovascular Research (DZHK), Partner site Hamburg/Lübeck/Kiel, Hamburg, Germany.|Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Mainz, Germany.
Karl
K
Lackner
Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Sasha
S
Singh
Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Paul M
PM
Ridker
University Heart Center Hamburg, Clinic for General and Interventional Cardiology, Hamburg, Germany.|German Center for Cardiovascular Research (DZHK), Partner site Hamburg/Lübeck/Kiel, Hamburg, Germany.
Stefan
S
Blankenberg
Center for Complex Networks Research and Department of Physics, Northeastern University, Boston, MA, USA.|Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Boston, MA, USA.|Department of Theoretical Physics, Budapest University of Technology and Economics, Budapest, Hungary.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.|Center for Network Science, Central European University, Budapest, Hungary.
Albert-László
AL
Barabási
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Joseph
J
Loscalzo
D002318:Cardiovascular Diseases / Q000378:metabolism*; D058068:Endophenotypes / Q000378:metabolism*; D005355:Fibrosis / Q000378:metabolism; D053263:Gene Regulatory Networks / Q000502:physiology; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D013927:Thrombosis / Q000378:metabolism
D058847:Inflammasomes