liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Gene Expression Profiling of Human Atherosclerosis
Linköping University, Department of Physics, Chemistry and Biology, Computational Biology . Linköping University, The Institute of Technology.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Atherosclerosis is a progressive inflammatory disease that causes lipid accumulation in the arterial wall, leading to the formation of plaques. The clinical manifestations of plaque rupture—stroke and myocardial infarction—are increasing worldwide and pose an enormous economic burden for society. Atherosclerosis development reflects a complex interaction between environmental exposures and genetic predisposition. To understand this complexity, we hypothesized that a top-down approach—one in which all molecular activities that drive atherosclerosis are examined simultaneously—is necessary to highlight those that are clinically relevant. To this end, we performed whole-genome expression profiling in multiple tissues isolated from patients with coronary artery disease (CAD).

In the Stockholm Atherosclerosis Gene Expression (STAGE) study, biopsies of five tissues (arterial wall with and without atherosclerotic lesions, liver, skeletal muscle and visceral fat) were isolated from 124 CAD patients undergoing coronary artery bypass grafting surgery (CABG) at the Karolinska University Hospital, Solna and carotid lesions from 39 patients undergoing carotid artery surgery at Stockholm Söder Hospital. Detailed clinical characteristics of these patients were assembled together with a total of 303 global gene expression profiles obtained with the Affymetrix GeneChip platform.

In paper 1, a two-way clustering analysis of the data identified 60 tissue clusters of functionally related genes. One cluster, partly present in both visceral fat and atherosclerotic lesions, related to atherosclerosis severity as judged by coronary angiograms. Many of the genes in that cluster were also present in a carotid lesion cluster relating to intima-media thickness (IMT) in the carotid patients. The union of all three clusters relating to extent of atherosclerosis—referred to as the “A-module”—was overrepresented with genes belonging to the transendothelial migration of leukocyte (TEML) pathway. The transcription co-factor, Lim domain binding 2 (LDB2), was identified as putative regulator of the A-module and TEML pathway in validation studies including Ldb2-/- mice.

In paper 2, we investigated the increased incidence of postoperative complications in CABG patients with diabetes. Using the STAGE compendium, we identified an anti-inflammatory marker, dual-specificity phosphatase 1 (DUSP1), as a novel preoperative blood marker of risk for a prolonged hospital stay after CABG.

In paper 3, plaque age was determined with C14-dating in the carotid patients. Interestingly, the strongest correlation with plaque age was not the age of the patients or IMT. Rather, the strongest correlations were with plasma insulin levels and inflammatory gene expression.

Taken together, the findings in this thesis show that a top-down approach using multi-tissue gene expression profiling in CAD and C14-dating of plaques can contribute to a better understanding of the molecular processes underlying atherosclerosis development and to the identification of clinically useful biomarkers.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2009. , 43 p.
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1282
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:liu:diva-52085ISBN: 978-91-7393-502-9 (print)OAI: oai:DiVA.org:liu-52085DiVA: diva2:279391
Public defence
2009-12-18, Thoraxaulan, Karolinska Universitetssjukhuset, Solna, N2:U1, Stockholm, 09:00 (English)
Opponent
Supervisors
Available from: 2009-12-03 Created: 2009-12-03 Last updated: 2009-12-07Bibliographically approved
List of papers
1. 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
Open this publication in new window or tab >>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
Show others...
2009 (English)In: PLoS Genetics, ISSN 1553-7390, Vol. 5, no 12, e1000754- p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
PLoS Genetics, 2009
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-52084 (URN)10.1371/journal.pgen.1000754 (DOI)
Note
On the day of the defence day the status of this article was: In Press.Available from: 2009-12-03 Created: 2009-12-03 Last updated: 2009-12-07Bibliographically approved
2. Dual-Specificity Phosphatase-1—An Anti-Inflammatory Marker in Blood Independently Predicting Prolonged Postoperative Stay after Coronary Artery Bypass Grafting: DUSP1 – A Preoperative Blood Marker of Postoperative Stay
Open this publication in new window or tab >>Dual-Specificity Phosphatase-1—An Anti-Inflammatory Marker in Blood Independently Predicting Prolonged Postoperative Stay after Coronary Artery Bypass Grafting: DUSP1 – A Preoperative Blood Marker of Postoperative Stay
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Objectives: Perform multi-organ expression profiling to identify gene markers predicting postoperative complications and hospitalization after coronary artery by-pass grafting (CABG) surgery.

Background: Identifying patients who are at increased risk of morbidity and prolonged post-operative stay is of interest from both health-economic and individual patient perspectives. Patients with diabetes often present with inflammatory conditions and have prolonged hospitalization after CABG. The recent development of technologies to generate high-dimensional data provides an opportunity to identify preoperative markers that can be used to help optimize preoperative planning to minimize postoperative complications.

Methods: We analyzed 198 whole-genome expression profiles of liver, skeletal muscle, and visceral fat isolated from 66 patients undergoing CABG in the Stockholm Atherosclerosis Gene Expression (STAGE) study. The findings were validated in pre-operative blood samples isolated from 181 patients undergoing CABG at Tartu University Hospital.

Results: As shown in other studies, diabetic CABG patients in the STAGE cohort also had prolonged hospitalization time (P<0.02). Out of ~50 000 mRNAs measures in the liver, skeletal muscle and visceral fat in 66 STAGE patients, the mRNA levels of anti-inflammatory gene dual specificity phosphatase-1 (DUSP1) correlated independently with post-operative rehabilitation and separated the patients into those with normal (8 days) and prolonged hospitalization (>8 days). In the validation cohort, preoperative blood levels of DUSP1 separated patients with short and long hospitalization stay (P=9x10-10).

Conclusions: From genome scans in three separate organs, we identified the anti-inflammatory gene DUSP1 as a pre-operative marker indicating risk for prolonged postoperative stay after CABG.

Keyword
Coronary artery disease, coronary artery by-pass grafting, postoperative stay, postoperative complication, gene expression profiling, dual-specificity phosphatase
National Category
Other Biological Topics
Identifiers
urn:nbn:se:liu:diva-51916 (URN)
Available from: 2009-12-03 Created: 2009-11-24 Last updated: 2009-12-03Bibliographically approved
3. Carbon-14 Dating to Determine Carotid Plaque Age: Carbon-14 Dating of Carotid Plaques
Open this publication in new window or tab >>Carbon-14 Dating to Determine Carotid Plaque Age: Carbon-14 Dating of Carotid Plaques
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Rationale: The exact nature of atherosclerotic plaque development and the molecular mechanisms that lead to clinical manifestations of carotid stenosis are unclear. After nuclear bomb tests in the 1950s, atmospheric 14C concentrations rapidly increased. Since then, the concentrations have been declining, and the curve of declination can be used to date biological samples synthesized during the last five to six decades.

Objective: To investigate plaque age as a novel characteristic of atherosclerotic plaques in patients with carotid stenosis.

Methods and Results: Carotid plaques from 29 well-characterized endarterectomy patients with symptomatic carotid stenosis were analyzed by accelerator mass spectrometry, and global gene expression of 25 plaque samples was profiled with HG-U133 Plus 2.0 arrays. The average plaque age was 9.3 years, and inter- and intrasample standard variations were low (1–3.5 years); thus, most of the plaques were generated 5–15 years before surgery. Plaque age was not associated with patient age or plaque size, determined by intima-media thickness, but was inversely related to plasma insulin levels (P=0.0014). A cluster of functionally related genes enriched with genes involved in immune responses was activated in plaques with low plaque age, as were oxidative phosphorylation genes.

Conclusion: Patients with mild insulin resistance have increased immune and inflammatory gene activity in their carotid plaques causing them to become instable, rapidly progressing into clinical manifestations at a relatively young age. These results show that plaque age, determined by 14C dating, is a novel and important characteristic of atherosclerotic plaques that will improve our understanding of the clinical significance and molecular underpinnings of atherosclerosis.

Keyword
gene expression profiling, carotid stenosis, atherosclerosis, 14C dating, insulin resistance
National Category
Other Biological Topics
Identifiers
urn:nbn:se:liu:diva-51917 (URN)
Available from: 2009-12-03 Created: 2009-11-24 Last updated: 2009-12-03Bibliographically approved

Open Access in DiVA

Gene Expression Profiling of Human Atherosclerosis(564 kB)1479 downloads
File information
File name FULLTEXT01.pdfFile size 564 kBChecksum SHA-512
f37063452712daf9e68a87dad5d4bb53e53800012fda02593881453af1e96e9e3be5dbb6dabcf0f0a423db8da1953c4e6135a8e5776968fba83cd43a51f56c92
Type fulltextMimetype application/pdf
Cover(684 kB)50 downloads
File information
File name COVER01.pdfFile size 684 kBChecksum SHA-512
84acdf6d76fc4e73a05be700e002492e5b3774bca0c4751d564e8543ab735ace9e5dd1b56bec6789df149d6ced08ee6afe659875044ce46f9716b64aebd2c778
Type coverMimetype application/pdf

Authority records BETA

Hägg, Sara

Search in DiVA

By author/editor
Hägg, Sara
By organisation
Computational Biology The Institute of Technology
Natural Sciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 1479 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 1159 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf