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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Genet. | doi: 10.3389/fgene.2019.00916

An integrated system biology approach yields drug repositioning candidates for the treatment of heart failure

Guodong Yang1, Aiqun Ma2 and  Zhaohui S. Qin3*
  • 1Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, United States
  • 2Department of Cardiovascular Medicine, First Affiliated Hospital of Xi’an Jiaotong University, China
  • 3Biostatistics and Bioinformatics, Emory University, United States

Identifying effective pharmacologic treatments for heart failure (HF) patients remains critically important. Given the development of drugs de novo is expensive and time-consuming, drug repositioning has become an increasingly important branch. In the present study, we propose a two-step drug repositioning pipeline and investigate the novel therapeutic effects of existing drugs approved by the U.S Food and Drug Administration to discover potential therapeutic drugs for HF. In the first step, we compared the gene expression pattern of HF patients with drug-induced gene expression profiles to obtain preliminary candidates. In the second step, we performed a systems biology approach based on the known protein-protein interaction information and targets of drugs to narrow down preliminary candidates to obtain final candidates. Drug set enrichment analysis and literature search were applied to assess the performance of our repositioning approach. We also constructed a mode of action network for each candidate and performed pathway analysis for each candidate using genes contained in their mode of action network to uncover pathways that potentially reflect the mechanisms of candidates’ therapeutic efficacy to HF. We discovered numerous preliminary candidates, some of which are used in clinical practice and supported by literature. The final candidates contained nearly all of the preliminary candidates supported by previous studies. Drug set enrichment analysis and literature search support the validity of our repositioning approach. The mode of action network for each candidate not only displayed the underlying mechanisms of drug efficacy, but uncovered potential biomarkers and therapeutic targets for HF. Our two-step drug repositioning approach is efficient to find candidates with potential therapeutic efficiency to HF supported by literature and might be of particular use in the discovery of novel effective pharmacologic therapies for HF.

Keywords: Heart Failure, Drug Repositioning, Gene signature, Systems Biology, connectivity map

Received: 29 May 2019; Accepted: 29 Aug 2019.

Copyright: © 2019 Yang, Ma and Qin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Zhaohui S. Qin, Emory University, Biostatistics and Bioinformatics, Atlanta, 30322, Georgia, United States,