Integrated systems approach identifies risk regulatory pathways and key regulators in coronary artery disease

J Mol Med (Berl). 2015 Dec;93(12):1381-90. doi: 10.1007/s00109-015-1315-x. Epub 2015 Jul 26.


Coronary artery disease (CAD) is the most common type of heart disease. However, the molecular mechanisms of CAD remain elusive. Regulatory pathways are known to play crucial roles in many pathogenic processes. Thus, inferring risk regulatory pathways is an important step toward elucidating the mechanisms underlying CAD. With advances in high-throughput data, we developed an integrated systems approach to identify CAD risk regulatory pathways and key regulators. Firstly, a CAD-related core subnetwork was identified from a curated transcription factor (TF) and microRNA (miRNA) regulatory network based on a random walk algorithm. Secondly, candidate risk regulatory pathways were extracted from the subnetwork by applying a breadth-first search (BFS) algorithm. Then, risk regulatory pathways were prioritized based on multiple CAD-associated data sources. Finally, we also proposed a new measure to prioritize upstream regulators. We inferred that phosphatase and tensin homolog (PTEN) may be a key regulator in the dysregulation of risk regulatory pathways. This study takes a closer step than the identification of disease subnetworks or modules. From the risk regulatory pathways, we could understand the flow of regulatory information in the initiation and progression of the disease. Our approach helps to uncover its potential etiology.

Key messages: We developed an integrated systems approach to identify risk regulatory pathways. We proposed a new measure to prioritize the key regulators in CAD. PTEN may be a key regulator in dysregulation of the risk regulatory pathways.

Keywords: Coronary artery disease; Regulatory pathway; Systems biology; Transcription factor; miRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Cluster Analysis
  • Computational Biology / methods
  • Coronary Artery Disease / genetics*
  • Coronary Artery Disease / metabolism*
  • Datasets as Topic
  • Gene Expression Profiling / methods
  • Gene Expression Regulation*
  • Gene Regulatory Networks
  • Humans
  • MicroRNAs / genetics
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Protein Interaction Mapping / methods
  • Protein Interaction Maps
  • Signal Transduction*
  • Systems Biology / methods*
  • Transcription Factors / metabolism


  • MicroRNAs
  • Transcription Factors
  • PTEN Phosphohydrolase