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dc.contributor.authorHägg, Sara
dc.contributor.authorSkogsberg, Josefin
dc.contributor.authorLundström, Jesper
dc.contributor.authorNoori, Peri
dc.contributor.authorNilsson, Roland
dc.contributor.authorZhong, Hua
dc.contributor.authorMaleki, Shohreh
dc.contributor.authorShang, Ming-Mei
dc.contributor.authorBrinne, Björn
dc.contributor.authorBradshaw, Maria
dc.contributor.authorBajic, Vladimir B.
dc.contributor.authorSamnegård, Ann
dc.contributor.authorSilveira, Angela
dc.contributor.authorKaplan, Lee M.
dc.contributor.authorGigante, Bruna
dc.contributor.authorLeander, Karin
dc.contributor.authorde Faire, Ulf
dc.contributor.authorRosfors, Stefan
dc.contributor.authorLockowandt, Ulf
dc.contributor.authorLiska, Jan
dc.contributor.authorKonrad, Peter
dc.contributor.authorTakolander, Rabbe
dc.contributor.authorFranco-Cereceda, Anders
dc.contributor.authorSchadt, Eric E.
dc.contributor.authorIvert, Torbjörn
dc.contributor.authorHamsten, Anders
dc.contributor.authorTegnér, Jesper
dc.contributor.authorBjörkegren, Johan
dc.date.accessioned2014-08-27T09:44:23Z
dc.date.available2014-08-27T09:44:23Z
dc.date.issued2009-12-04
dc.identifier.citationHägg S, Skogsberg J, Lundström J, Noori P, Nilsson R, et al. (2009) Multi-Organ Expression Profiling Uncovers a Gene Module in Coronary Artery Disease Involving Transendothelial Migration of Leukocytes and LIM Domain Binding 2: The Stockholm Atherosclerosis Gene Expression (STAGE) Study. PLoS Genet 5: e1000754. doi:10.1371/journal.pgen.1000754.
dc.identifier.issn15537390
dc.identifier.pmid19997623
dc.identifier.doi10.1371/journal.pgen.1000754
dc.identifier.urihttp://hdl.handle.net/10754/325276
dc.description.abstractEnvironmental exposures filtered through the genetic make-up of each individual alter the transcriptional repertoire in organs central to metabolic homeostasis, thereby affecting arterial lipid accumulation, inflammation, and the development of coronary artery disease (CAD). The primary aim of the Stockholm Atherosclerosis Gene Expression (STAGE) study was to determine whether there are functionally associated genes (rather than individual genes) important for CAD development. To this end, two-way clustering was used on 278 transcriptional profiles of liver, skeletal muscle, and visceral fat (n =66/tissue) and atherosclerotic and unaffected arterial wall (n =40/tissue) isolated from CAD patients during coronary artery bypass surgery. The first step, across all mRNA signals (n =15,042/12,621 RefSeqs/genes) in each tissue, resulted in a total of 60 tissue clusters (n= 3958 genes). In the second step (performed within tissue clusters), one atherosclerotic lesion (n =49/48) and one visceral fat (n =59) cluster segregated the patients into two groups that differed in the extent of coronary stenosis (P=0.008 and P=0.00015). The associations of these clusters with coronary atherosclerosis were validated by analyzing carotid atherosclerosis expression profiles. Remarkably, in one cluster (n =55/54) relating to carotid stenosis (P =0.04), 27 genes in the two clusters relating to coronary stenosis were confirmed (n= 16/17, P<10 -27and-30). Genes in the transendothelial migration of leukocytes (TEML) pathway were overrepresented in all three clusters, referred to as the atherosclerosis module (A-module). In a second validation step, using three independent cohorts, the Amodule was found to be genetically enriched with CAD risk by 1.8-fold (P<0.004). The transcription co-factor LIM domain binding 2 (LDB2) was identified as a potential high-hierarchy regulator of the A-module, a notion supported by subnetwork analysis, by cellular and lesion expression of LDB2, and by the expression of 13 TEML genes in Ldb2-deficient arterial wall. Thus, the A-module appears to be important for atherosclerosis development and, together with LDB2, merits further attention in CAD research. 2009 Hgg et al.
dc.language.isoen
dc.publisherPublic Library of Science (PLoS)
dc.rightsHägg et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.rightsArchived with thanks to PLoS Genetics
dc.subjectlim domain binding 2
dc.subjectmessenger RNA
dc.subjecttranscription factor
dc.subjectunclassified drug
dc.subjectadult
dc.subjectaged
dc.subjectbioinformatics
dc.subjectcarotid artery obstruction
dc.subjectcell migration
dc.subjectcontrolled study
dc.subjectcoronary artery bypass surgery
dc.subjectcoronary artery disease
dc.subjectcoronary artery obstruction
dc.subjectdisease course
dc.subjectgene cluster
dc.subjectgene expression profiling
dc.subjectgenetic risk
dc.subjectgenetic transcription
dc.subjecthuman cell
dc.subjecthuman tissue
dc.subjectintraabdominal fat
dc.subjectleukocyte
dc.subjectmajor clinical study
dc.subjectskeletal muscle
dc.subjectvalidation study
dc.titleMulti-organ expression profiling uncovers a gene module in coronary artery disease involving transendothelial migration of leukocytes and LIM domain binding 2: The Stockholm Atherosclerosis Gene Expression (STAGE) study
dc.typeArticle
dc.contributor.departmentComputational Bioscience Research Center (CBRC)
dc.identifier.journalPLoS Genetics
dc.identifier.pmcidPMC2780352
dc.eprint.versionPublisher's Version/PDF
dc.contributor.institutionComputational Medicine Group, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
dc.contributor.institutionDepartment of Computational Biology, Linkping Institute of Technology, Linkping University, Linkping, Sweden
dc.contributor.institutionClinical Gene Networks AB, Karolinska Science Park, Stockholm, Sweden
dc.contributor.institutionRosetta Inpharmatics, Merck, Seattle, WA, United States
dc.contributor.institutionSouth African National Bioinformatics Institute (SANBI), University of the Western Cape, Cape Town, South Africa
dc.contributor.institutionDepartment of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
dc.contributor.institutionCardiovascular Genetics Group, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
dc.contributor.institutionMassachusetts General Hospital (MGH), Department of Medicine, Harvard Medical School, Boston, MA, United States
dc.contributor.institutionDepartment of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
dc.contributor.institutionDepartment of Clinical Physiology, Stockholm Sder Hospital, Karolinska Institutet, Stockholm, Sweden
dc.contributor.institutionDepartment of Thoracic Surgery and Anesthesiology, Karolinska University Hospital, Stockholm, Sweden
dc.contributor.institutionDepartment of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
dc.contributor.institutionDepartment of Surgery, Stockholm Sder Hospital, Karolinska Institutet, Stockholm, Sweden
dc.contributor.affiliationKing Abdullah University of Science and Technology (KAUST)
kaust.personBajic, Vladimir B.
refterms.dateFOA2018-06-14T03:32:58Z


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