title: Illuminating drug action by network integration of disease genes: a case study of myocardial infarction.
abstract: Drug discovery has produced many successful therapeutic agents; however, most of these drugs were developed without a deep understanding of the system-wide mechanisms of action responsible for their indications. Gene-disease associations produced by molecular and genetic studies of complex diseases provide great opportunities for a system-level understanding of drug activity. In this study, we focused on acute myocardial infarction (MI) and conducted an integrative network analysis to illuminate drug actions. We integrated MI drugs, MI drug interactors, drug targets, and MI disease genes into the human interactome and showed that MI drug targets are significantly proximate to MI disease proteins. We then constructed a bipartite network of MI-related drug targets and MI disease proteins and derived 12 drug-target-disease (DTD) modules. We assessed the biological relevance of these modules and demonstrated the benefits of incorporating disease genes. The results indicate that DTD modules provide insights into the mechanisms of action of MI drugs and the cardiovascular (side) effects of non-MI drugs.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA. jloscalzo@partners.org.
authors.forename: Rui-Sheng
authors.initials: RS
authors.lastname: Wang
authors.affiliation: Department of Medicine, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA. jloscalzo@partners.org.
authors.forename: Joseph
authors.initials: J
authors.lastname: Loscalzo
mesh_terms: D000465:Algorithms; D019295:Computational Biology / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D053263:Gene Regulatory Networks / Q000187:drug effects*; D006801:Humans; D008954:Models, Biological; D009203:Myocardial Infarction / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps