Cross-Tissue Regulatory Gene Networks in Coronary Artery Disease

Husain A. Talukdar, Hassan Foroughi Asl, Rajeev K. Jain, Raili Ermel, Arno Ruusalepp, Oscar Franzén, Brian A. Kidd, Ben Readhead, Chiara Giannarelli, Jason C. Kovacic, Torbjörn Ivert, Joel T. Dudley, Mete Civelek, Aldons J. Lusis, Eric E. Schadt, Josefin Skogsberg, Tom Michoel, Johan L.M. Björkegren

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

Summary Inferring molecular networks can reveal how genetic perturbations interact with environmental factors to cause common complex diseases. We analyzed genetic and gene expression data from seven tissues relevant to coronary artery disease (CAD) and identified regulatory gene networks (RGNs) and their key drivers. By integrating data from genome-wide association studies, we identified 30 CAD-causal RGNs interconnected in vascular and metabolic tissues, and we validated them with corresponding data from the Hybrid Mouse Diversity Panel. As proof of concept, by targeting the key drivers AIP, DRAP1, POLR2I, and PQBP1 in a cross-species-validated, arterial-wall RGN involving RNA-processing genes, we re-identified this RGN in THP-1 foam cells and independent data from CAD macrophages and carotid lesions. This characterization of the molecular landscape in CAD will help better define the regulation of CAD candidate genes identified by genome-wide association studies and is a first step toward achieving the goals of precision medicine.

Original languageEnglish (US)
Pages (from-to)196-208
Number of pages13
JournalCell Systems
Volume2
Issue number3
DOIs
StatePublished - Mar 23 2016

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology
  • Cell Biology

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