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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
Linköping University, Department of Physics, Chemistry and Biology, Computational Biology . Linköping University, The Institute of Technology.
Department of Cardiothoracic Surgery and Anaesthesiology and Department of Molecular Medicine and Surgery, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden.
Computational Medicine Group (, Center for Molecular Medicine, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden. (Tegnér-Björkegren)
Computational Medicine Group (, Center for Molecular Medicine, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden. (Tegnér-Björkegren)
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(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 [en]
Coronary artery disease, coronary artery by-pass grafting, postoperative stay, postoperative complication, gene expression profiling, dual-specificity phosphatase
National Category
Other Biological Topics
URN: urn:nbn:se:liu:diva-51916OAI: diva2:278116
Available from: 2009-12-03 Created: 2009-11-24 Last updated: 2009-12-03Bibliographically approved
In thesis
1. Gene Expression Profiling of Human Atherosclerosis
Open this publication in new window or tab >>Gene Expression Profiling of Human Atherosclerosis
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.
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1282
National Category
Natural Sciences
urn:nbn:se:liu:diva-52085 (URN)978-91-7393-502-9 (ISBN)
Public defence
2009-12-18, Thoraxaulan, Karolinska Universitetssjukhuset, Solna, N2:U1, Stockholm, 09:00 (English)
Available from: 2009-12-03 Created: 2009-12-03 Last updated: 2009-12-07Bibliographically approved

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