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  • Hägg, Sara,1977-Linköpings universitet,Biologiska Beräkningar,Tekniska högskolan (author)

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

  • Article/chapterEnglish2009

Publisher, publication year, extent ...

  • 2009-12-04
  • PLoS Genetics,2009
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:liu-52084
  • https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-52084URI
  • https://doi.org/10.1371/journal.pgen.1000754DOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:119874102URI

Supplementary language notes

  • Language:English
  • Summary in:English

Part of subdatabase

Classification

  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • On the day of the defence day the status of this article was: In Press.
  • 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 A-module 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, cellular and lesion expression of LDB2, and 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.

Subject headings and genre

  • NATURAL SCIENCES
  • NATURVETENSKAP

Added entries (persons, corporate bodies, meetings, titles ...)

  • Skogsberg, JosefinKarolinska Institutet (author)
  • Lundström, JesperLinköpings universitet,Biologiska Beräkningar,Tekniska högskolan(Swepub:liu)jeslu06 (author)
  • Noori, PeriKarolinska Institutet (author)
  • Nilsson, RolandKarolinska Institutet,Linköpings universitet,Biologiska Beräkningar,Tekniska högskolan(Swepub:liu)rolni12 (author)
  • Zhong, HuaRosetta Inpharmatics, LLC, a Merck & Co., Inc, Seattle, USA (author)
  • Maleki, ShohrehKarolinska Institutet (author)
  • Shang, Ming-MeiKarolinska Institutet (author)
  • Brinne, BjörnKarolinska Institutet,Linköpings universitet,Biologiska Beräkningar,Tekniska högskolan(Swepub:liu)bjobr93 (author)
  • Bradshaw, MariaLinköpings universitet,Biologiska Beräkningar,Tekniska högskolan(Swepub:liu)marbr27 (author)
  • Bajic, Vladimir B.South African National Bioinformatics Institute (SANBI), University of the Western Cape, Cape Town, South Africa, and Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Kingdom of Saudi Arabia (author)
  • Samnegård, AnnKarolinska Institutet (author)
  • Silveira, AngelaKarolinska Institutet (author)
  • Kaplan, Lee M.Massachusetts General Hospital (MGH) Weight Center and Department of Medicine, Harvard Medical School, Boston, USA (author)
  • Gigante, BrunaDepartment of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (author)
  • Leander, KarinKarolinska Institutet (author)
  • de Faire, UlfKarolinska Institutet (author)
  • Rosfors, StefanKarolinska Institutet (author)
  • Lockowandt, UlfKarolinska Institutet (author)
  • Liska, JanKarolinska Institutet (author)
  • Konrad, PeterKarolinska Institutet (author)
  • Takolander, RabbeDepartment of Surgery, Stockholm Söder Hospital, Karolinska Institutet, Stockholm, Sweden (author)
  • Franco-Cereceda, AndersKarolinska Institutet (author)
  • Schadt, Eric E.Rosetta Inpharmatics, LLC, a Merck & Co., Inc, Seattle, USA (author)
  • Ivert, TorbjörnKarolinska Institutet (author)
  • Hamsten, AndersKarolinska Institutet (author)
  • Tegnér, JesperKarolinska Institutet,Linköpings universitet,Biologiska Beräkningar,Tekniska högskolan(Swepub:liu)jeste12 (author)
  • Björkegren, JohanKarolinska Institutet (author)
  • Linköpings universitetBiologiska Beräkningar (creator_code:org_t)

Related titles

  • In:PLoS Genetics: PLoS Genetics5:12, s. e1000754-1553-73901553-7404

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