title: Gene expression signatures, pathways and networks in carotid atherosclerosis.
abstract: BACKGROUND
  Embolism from unstable atheromas in the carotid bifurcation is a major cause of stroke. Here, we analysed gene expression in endarterectomies from patients with symptomatic (S) and asymptomatic (AS) carotid stenosis to identify pathways linked to plaque instability.
  
  
  METHODS
  Microarrays were prepared from plaques (n = 127) and peripheral blood samples (n = 96) of S and AS patients. Gene set enrichment, pathway mapping and network analyses of differentially expressed genes were performed.
  
  
  RESULTS
  These studies revealed upregulation of haemoglobin metabolism (P = 2.20E-05) and bone resorption (P = 9.63E-04) in S patients. Analysis of subgroups of patients indicated enrichment of calcification and osteoblast differentiation in S patients on statins, as well as inflammation and apoptosis in plaques removed >1 month compared to <2 weeks after symptom. By prediction profiling, a panel of 30 genes, mostly transcription factors, discriminated between plaques from S versus AS patients with 78% accuracy. By meta-analysis, common gene networks associated with atherosclerosis mapped to hypoxia, chemokines, calcification, actin cytoskeleton and extracellular matrix. A set of dysregulated genes (LMOD1, SYNPO2, PLIN2 and PPBP) previously not described in atherosclerosis were identified from microarrays and validated by quantitative PCR and immunohistochemistry.
  
  
  CONCLUSIONS
  Our findings confirmed a central role for inflammation and proteases in plaque instability, and highlighted haemoglobin metabolism and bone resorption as important pathways. Subgroup analysis suggested prolonged inflammation following the symptoms of plaque instability and calcification as a possible stabilizing mechanism by statins. In addition, transcriptional regulation may play an important role in the determination of plaque phenotype. The results from this study will serve as a basis for further exploration of molecular signatures in carotid atherosclerosis.
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Perisic
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Aldi
authors.affiliation: Translational Science Center, Personalized Healthcare and Biomarkers, R&D, Astra Zeneca, Stockholm, Sweden.
authors.forename: Y
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Molecular Genetics, Novo Nordisk, Copenhagen, Denmark.|Department of Medicine, Karolinska Institute, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Folkersen
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Razuvaev
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Roy
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Lengquist
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Åkesson
authors.affiliation: Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
authors.forename: C E
authors.initials: CE
authors.lastname: Wheelock
authors.affiliation: Department of Medicine, Karolinska Institute, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Maegdefessel
authors.affiliation: Department of Medicine, Karolinska Institute, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Gabrielsen
authors.affiliation: Department of Medicine, Karolinska Institute, Stockholm, Sweden.|Science for Life Laboratory, Department of Proteomics, School of Biotechnology, Royal Institute of Technology, Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Odeberg
authors.affiliation: Department of Medicine, Karolinska Institute, Stockholm, Sweden.
authors.forename: G K
authors.initials: GK
authors.lastname: Hansson
authors.affiliation: Department of Medicine, Karolinska Institute, Stockholm, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Paulsson-Berne
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
authors.forename: U
authors.initials: U
authors.lastname: Hedin
mesh_terms: D000368:Aged; D002340:Carotid Artery Diseases / Q000235:genetics*; D005260:Female; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D015398:Signal Transduction; D059467:Transcriptome
keywords: atherosclerosis; carotid plaques; gene expression; microarrays