title: Cross-Tissue Regulatory Gene Networks in Coronary Artery Disease.
abstract: 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.
authors.affiliation: Cardiovascular Genomics Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Husain A
authors.initials: HA
authors.lastname: Talukdar
authors.affiliation: Cardiovascular Genomics Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Hassan
authors.initials: H
authors.lastname: Foroughi Asl
authors.affiliation: Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, 51014 Tartu, Estonia.
authors.forename: Rajeev K
authors.initials: RK
authors.lastname: Jain
authors.affiliation: Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, 51014 Tartu, Estonia; Department of Cardiac Surgery, Tartu University Hospital, 51014 Tartu, Estonia.
authors.forename: Raili
authors.initials: R
authors.lastname: Ermel
authors.affiliation: Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, 51014 Tartu, Estonia; Department of Cardiac Surgery, Tartu University Hospital, 51014 Tartu, Estonia; Clinical Gene Networks AB, 114 44 Stockholm, Sweden.
authors.forename: Arno
authors.initials: A
authors.lastname: Ruusalepp
authors.affiliation: Clinical Gene Networks AB, 114 44 Stockholm, Sweden; Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Oscar
authors.initials: O
authors.lastname: Franzén
authors.affiliation: Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Kidd
authors.affiliation: Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Readhead
authors.affiliation: Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Chiara
authors.initials: C
authors.lastname: Giannarelli
authors.affiliation: The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Kovacic
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Thoracic Surgery, Karolinska University Hospital, 171 76 Stockholm, Sweden.
authors.forename: Torbjörn
authors.initials: T
authors.lastname: Ivert
authors.affiliation: Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Joel T
authors.initials: JT
authors.lastname: Dudley
authors.affiliation: Departments of Medicine, Cardiology, Human Genetics, Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90024, USA.
authors.forename: Mete
authors.initials: M
authors.lastname: Civelek
authors.affiliation: Departments of Medicine, Cardiology, Human Genetics, Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90024, USA.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.affiliation: Clinical Gene Networks AB, 114 44 Stockholm, Sweden; Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.affiliation: Cardiovascular Genomics Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Josefin
authors.initials: J
authors.lastname: Skogsberg
authors.affiliation: Clinical Gene Networks AB, 114 44 Stockholm, Sweden; Division of Genetics and Genomics, The Roslin Institute, University of Edinburgh, Edinburgh EH25 9RG, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Michoel
authors.affiliation: Cardiovascular Genomics Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, 51014 Tartu, Estonia; Clinical Gene Networks AB, 114 44 Stockholm, Sweden; Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Cardiovascular Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: johan.bjorkegren@mssm.edu.
authors.forename: Johan L M
authors.initials: JL
authors.lastname: Björkegren
mesh_terms: D000818:Animals; D002352:Carrier Proteins; D003324:Coronary Artery Disease; D004268:DNA-Binding Proteins; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins; D012097:Repressor Proteins
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C484382:Drap1 protein, mouse; D009687:Nuclear Proteins; C492272:Pqbp1 protein, mouse; D012097:Repressor Proteins