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.
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 S...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2009-12-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC2780352?pdf=render |
| _version_ | 1819060267799019520 |
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| author | Sara Hägg Josefin Skogsberg Jesper Lundström Peri Noori Roland Nilsson Hua Zhong Shohreh Maleki Ming-Mei Shang Björn Brinne Maria Bradshaw Vladimir B Bajic Ann Samnegård Angela Silveira Lee M Kaplan Bruna Gigante Karin Leander Ulf de Faire Stefan Rosfors Ulf Lockowandt Jan Liska Peter Konrad Rabbe Takolander Anders Franco-Cereceda Eric E Schadt Torbjörn Ivert Anders Hamsten Jesper Tegnér Johan Björkegren |
| author_facet | Sara Hägg Josefin Skogsberg Jesper Lundström Peri Noori Roland Nilsson Hua Zhong Shohreh Maleki Ming-Mei Shang Björn Brinne Maria Bradshaw Vladimir B Bajic Ann Samnegård Angela Silveira Lee M Kaplan Bruna Gigante Karin Leander Ulf de Faire Stefan Rosfors Ulf Lockowandt Jan Liska Peter Konrad Rabbe Takolander Anders Franco-Cereceda Eric E Schadt Torbjörn Ivert Anders Hamsten Jesper Tegnér Johan Björkegren |
| author_sort | Sara Hägg |
| collection | DOAJ |
| description | 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(-27 and-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, 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. |
| first_indexed | 2024-12-21T14:24:17Z |
| format | Article |
| id | doaj.art-a36a7f46d91547e2bc0f1a6cf6f69acd |
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| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-21T14:24:17Z |
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| publisher | Public Library of Science (PLoS) |
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| series | PLoS Genetics |
| spelling | doaj.art-a36a7f46d91547e2bc0f1a6cf6f69acd2022-12-21T19:00:42ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042009-12-01512e100075410.1371/journal.pgen.1000754Multi-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.Sara HäggJosefin SkogsbergJesper LundströmPeri NooriRoland NilssonHua ZhongShohreh MalekiMing-Mei ShangBjörn BrinneMaria BradshawVladimir B BajicAnn SamnegårdAngela SilveiraLee M KaplanBruna GiganteKarin LeanderUlf de FaireStefan RosforsUlf LockowandtJan LiskaPeter KonradRabbe TakolanderAnders Franco-CerecedaEric E SchadtTorbjörn IvertAnders HamstenJesper TegnérJohan BjörkegrenEnvironmental 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(-27 and-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, 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.http://europepmc.org/articles/PMC2780352?pdf=render |
| spellingShingle | Sara Hägg Josefin Skogsberg Jesper Lundström Peri Noori Roland Nilsson Hua Zhong Shohreh Maleki Ming-Mei Shang Björn Brinne Maria Bradshaw Vladimir B Bajic Ann Samnegård Angela Silveira Lee M Kaplan Bruna Gigante Karin Leander Ulf de Faire Stefan Rosfors Ulf Lockowandt Jan Liska Peter Konrad Rabbe Takolander Anders Franco-Cereceda Eric E Schadt Torbjörn Ivert Anders Hamsten Jesper Tegnér Johan Björkegren 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 Genetics |
| 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. |
| title_full | 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. |
| title_fullStr | 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. |
| title_full_unstemmed | 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. |
| title_short | 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. |
| title_sort | 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 |
| url | http://europepmc.org/articles/PMC2780352?pdf=render |
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