title: A quantitative approach to study indirect effects among disease proteins in the human protein interaction network.
abstract: BACKGROUND
  Systems biology makes it possible to study larger and more intricate systems than before, so it is now possible to look at the molecular basis of several diseases in parallel. Analyzing the interaction network of proteins in the cell can be the key to understand how complex processes lead to diseases. Novel tools in network analysis provide the possibility to quantify the key interacting proteins in large networks as well as proteins that connect them. Here we suggest a new method to study the relationships between topology and functionality of the protein-protein interaction network, by identifying key mediator proteins possibly maintaining indirect relationships among proteins causing various diseases.
  
  
  RESULTS
  Based on the i2d and OMIM databases, we have constructed (i) a network of proteins causing five selected diseases (DP, disease proteins) plus their interacting partners (IP, non-disease proteins), the DPIP network and (ii) a protein network showing only these IPs and their interactions, the IP network. The five investigated diseases were (1) various cancers, (2) heart diseases, (3) obesity, (4) diabetes and (5) autism. We have quantified the number and strength of IP-mediated indirect effects between the five groups of disease proteins and hypothetically identified the most important mediator proteins linking heart disease to obesity or diabetes in the IP network. The results present the relationship between mediator role and centrality, as well as between mediator role and functional properties of these proteins.
  
  
  CONCLUSIONS
  We show that a protein which plays an important indirect mediator role between two diseases is not necessarily a hub in the PPI network. This may suggest that, even if hub proteins and disease proteins are trivially of great interest, mediators may also deserve more attention, especially if disease-disease associations are to be understood. Identifying the hubs may not be sufficient to understand particular pathways. We have found that the mediators between heart diseases and obesity, as well as heart diseases and diabetes are of relatively high functional importance in the cell. The mediator proteins suggested here should be experimentally tested as products of hypothetical disease-related proteins.
authors.affiliation: The Microsoft Research, University of Trento, Centre for Computational and Systems Biology, Piazza Manci 17, 38100 Trento, Italy.
authors.forename: Thanh-Phuong
authors.initials: TP
authors.lastname: Nguyen
authors.forename: Ferenc
authors.initials: F
authors.lastname: Jordán
mesh_terms: D004194:Disease; D006801:Humans; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011506:Proteins / Q000378:metabolism*; D015203:Reproducibility of Results; D049490:Systems Biology / Q000379:methods*
chemical_list: D011506:Proteins