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

Handle URI:
http://hdl.handle.net/10754/325276
Title:
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
Authors:
Hägg, Sara; Skogsberg, Josefin; Lundström, Jesper; Noori, Peri; Nilsson, Roland; Zhong, Hua; Maleki, Shohreh; Shang, Ming-Mei; Brinne, Björn; Bradshaw, Maria; Bajic, Vladimir B. ( 0000-0001-5435-4750 ) ; Samnegård, Ann; Silveira, Angela; Kaplan, Lee M.; Gigante, Bruna; Leander, Karin; de Faire, Ulf; Rosfors, Stefan; Lockowandt, Ulf; Liska, Jan; Konrad, Peter; Takolander, Rabbe; Franco-Cereceda, Anders; Schadt, Eric E.; Ivert, Torbjörn; Hamsten, Anders; Tegnér, Jesper; Björkegren, Johan
Abstract:
Environmental 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.
KAUST Department:
Computational Bioscience Research Center (CBRC)
Citation:
Hägg 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.
Publisher:
Public Library of Science (PLoS)
Journal:
PLoS Genetics
Issue Date:
4-Dec-2009
DOI:
10.1371/journal.pgen.1000754
PubMed ID:
19997623
PubMed Central ID:
PMC2780352
Type:
Article
ISSN:
15537390
Appears in Collections:
Articles; Computational Bioscience Research Center (CBRC)

Full metadata record

DC FieldValue Language
dc.contributor.authorHägg, Saraen
dc.contributor.authorSkogsberg, Josefinen
dc.contributor.authorLundström, Jesperen
dc.contributor.authorNoori, Perien
dc.contributor.authorNilsson, Rolanden
dc.contributor.authorZhong, Huaen
dc.contributor.authorMaleki, Shohrehen
dc.contributor.authorShang, Ming-Meien
dc.contributor.authorBrinne, Björnen
dc.contributor.authorBradshaw, Mariaen
dc.contributor.authorBajic, Vladimir B.en
dc.contributor.authorSamnegård, Annen
dc.contributor.authorSilveira, Angelaen
dc.contributor.authorKaplan, Lee M.en
dc.contributor.authorGigante, Brunaen
dc.contributor.authorLeander, Karinen
dc.contributor.authorde Faire, Ulfen
dc.contributor.authorRosfors, Stefanen
dc.contributor.authorLockowandt, Ulfen
dc.contributor.authorLiska, Janen
dc.contributor.authorKonrad, Peteren
dc.contributor.authorTakolander, Rabbeen
dc.contributor.authorFranco-Cereceda, Andersen
dc.contributor.authorSchadt, Eric E.en
dc.contributor.authorIvert, Torbjörnen
dc.contributor.authorHamsten, Andersen
dc.contributor.authorTegnér, Jesperen
dc.contributor.authorBjörkegren, Johanen
dc.date.accessioned2014-08-27T09:44:23Z-
dc.date.available2014-08-27T09:44:23Z-
dc.date.issued2009-12-04en
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.en
dc.identifier.issn15537390en
dc.identifier.pmid19997623en
dc.identifier.doi10.1371/journal.pgen.1000754en
dc.identifier.urihttp://hdl.handle.net/10754/325276en
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.en
dc.language.isoenen
dc.publisherPublic Library of Science (PLoS)en
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.en
dc.rightsArchived with thanks to PLoS Geneticsen
dc.subjectlim domain binding 2en
dc.subjectmessenger RNAen
dc.subjecttranscription factoren
dc.subjectunclassified drugen
dc.subjectadulten
dc.subjectageden
dc.subjectbioinformaticsen
dc.subjectcarotid artery obstructionen
dc.subjectcell migrationen
dc.subjectcontrolled studyen
dc.subjectcoronary artery bypass surgeryen
dc.subjectcoronary artery diseaseen
dc.subjectcoronary artery obstructionen
dc.subjectdisease courseen
dc.subjectgene clusteren
dc.subjectgene expression profilingen
dc.subjectgenetic risken
dc.subjectgenetic transcriptionen
dc.subjecthuman cellen
dc.subjecthuman tissueen
dc.subjectintraabdominal faten
dc.subjectleukocyteen
dc.subjectmajor clinical studyen
dc.subjectskeletal muscleen
dc.subjectvalidation studyen
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) studyen
dc.typeArticleen
dc.contributor.departmentComputational Bioscience Research Center (CBRC)en
dc.identifier.journalPLoS Geneticsen
dc.identifier.pmcidPMC2780352en
dc.eprint.versionPublisher's Version/PDFen
dc.contributor.institutionComputational Medicine Group, Department of Medicine, Karolinska Institutet, Stockholm, Swedenen
dc.contributor.institutionDepartment of Computational Biology, Linkping Institute of Technology, Linkping University, Linkping, Swedenen
dc.contributor.institutionClinical Gene Networks AB, Karolinska Science Park, Stockholm, Swedenen
dc.contributor.institutionRosetta Inpharmatics, Merck, Seattle, WA, United Statesen
dc.contributor.institutionSouth African National Bioinformatics Institute (SANBI), University of the Western Cape, Cape Town, South Africaen
dc.contributor.institutionDepartment of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Swedenen
dc.contributor.institutionCardiovascular Genetics Group, Department of Medicine, Karolinska Institutet, Stockholm, Swedenen
dc.contributor.institutionMassachusetts General Hospital (MGH), Department of Medicine, Harvard Medical School, Boston, MA, United Statesen
dc.contributor.institutionDepartment of Environmental Medicine, Karolinska Institutet, Stockholm, Swedenen
dc.contributor.institutionDepartment of Clinical Physiology, Stockholm Sder Hospital, Karolinska Institutet, Stockholm, Swedenen
dc.contributor.institutionDepartment of Thoracic Surgery and Anesthesiology, Karolinska University Hospital, Stockholm, Swedenen
dc.contributor.institutionDepartment of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Swedenen
dc.contributor.institutionDepartment of Surgery, Stockholm Sder Hospital, Karolinska Institutet, Stockholm, Swedenen
dc.contributor.affiliationKing Abdullah University of Science and Technology (KAUST)en
kaust.authorBajic, Vladimir B.en

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