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Gene Expression Signatures, Pathways and Networks in Carotid Atherosclerosis

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Gene Expression Signatures, Pathways and Networks in Carotid Atherosclerosis Original Article doi: 10.1111/joim.12448 Gene expression signatures, pathways and networks in carotid atherosclerosis L. Perisic1, S. Aldi1,*, Y. Sun2,*, L. Folkersen3,4, A. Razuvaev1, J. Roy1, M. Lengquist1,S.Akesson1, C. E. Wheelock5, L. Maegdefessel4, A. Gabrielsen4, J. Odeberg4,6, G. K. Hansson4, G. Paulsson-Berne4 & U. Hedin1 From the 1Department of Molecular Medicine and Surgery, Karolinska Institute; 2Translational Science Center, Personalized Healthcare and Biomarkers, R&D, Astra Zeneca, Stockholm, Sweden; 3Department of Molecular Genetics, Novo Nordisk, Copenhagen, Denmark; 4Department of Medicine, Karolinska Institute; 5Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institute; and 6Science for Life Laboratory, Department of Proteomics, School of Biotechnology, Royal Institute of Technology, Stockholm, Sweden Abstract. Perisic L, Aldi S, Sun Y, Folkersen L, patients on statins, as well as inflammation and Razuvaev A, Roy J, Lengquist M, Akesson S, apoptosis in plaques removed >1 month compared Wheelock CE, Maegdefessel L, Gabrielsen A, to <2 weeks after symptom. By prediction profiling, Odeberg J, Hansson GK, Paulsson-Berne G, a panel of 30 genes, mostly transcription factors, Hedin U (Karolinska Institute, Stockholm; R&D, discriminated between plaques from S versus AS Astra Zeneca, Stockholm, Sweden; Novo Nordisk, patients with 78% accuracy. By meta-analysis, Copenhagen, Denmark; Karolinska Institute, common gene networks associated with Stockholm; Karolinska Institute, Stockholm; atherosclerosis mapped to hypoxia, chemokines, Royal Institute of Technology, Stockholm, calcification, actin cytoskeleton and extracellular Sweden). Gene expression signatures, pathways matrix. A set of dysregulated genes (LMOD1, and networks in carotid atherosclerosis. J Intern SYNPO2, PLIN2 and PPBP) previously not described Med 2015; doi: 10.1111/joim.12448. in atherosclerosis were identified from microarrays and validated by quantitative PCR and immuno- Background. Embolism from unstable atheromas in histochemistry. the carotid bifurcation is a major cause of stroke. Here, we analysed gene expression in endarterec- Conclusions. Our findings confirmed a central role tomies from patients with symptomatic (S) and for inflammation and proteases in plaque insta- asymptomatic (AS) carotid stenosis to identify bility, and highlighted haemoglobin metabolism pathways linked to plaque instability. and bone resorption as important pathways. Subgroup analysis suggested prolonged inflam- Methods. Microarrays were prepared from plaques mation following the symptoms of plaque insta- (n = 127) and peripheral blood samples (n = 96) of bility and calcification as a possible stabilizing S and AS patients. Gene set enrichment, pathway mechanism by statins. In addition, transcrip- mapping and network analyses of differentially tional regulation may play an important role in expressed genes were performed. the determination of plaque phenotype. The results from this study will serve as a basis for Results. These studies revealed upregulation of further exploration of molecular signatures in haemoglobin metabolism (P = 2.20E-05) and bone carotid atherosclerosis. resorption (P = 9.63E-04) in S patients. Analysis of subgroups of patients indicated enrichment of Keywords: atherosclerosis, carotid plaques, gene calcification and osteoblast differentiation in S expression, microarrays. cardiovascular disease. In order to improve identi- Introduction fication of individuals at risk and to facilitate the Atherosclerotic plaque rupture followed by myocar- development of future preventive therapeutic dial infarction or stroke is the major cause of strategies, there is a need for better understanding morbidity and mortality in patients with of the pathophysiology underlying the transition of atherosclerosis from clinically asymptomatic (AS) *These authors contributed equally. ª 2015 The Association for the Publication of the Journal of Internal Medicine 1 L. Perisic et al. Atherosclerosis transcriptome and stable lesions to symptomatic (S) and unstable clinical categories. Hence, factors determining disease [1]. plaque vulnerability and healing remain largely unknown. The unstable atheroma has previously been char- acterized by enhanced activity of proinflammatory The Biobank of Karolinska Endarterectomy (BiKE) T cells and macrophages, increased cytokine was established in 2002 for prospective collection release and secretion of matrix metalloproteinases of atherosclerotic plaque tissue and blood from (MMPs), thinning of the fibrous cap due to impaired patients undergoing carotid endarterectomy for collagen fibre formation, collagenolysis and cell high-grade carotid artery stenosis, with a database apoptosis. Together with haemodynamic forces, of clinical parameters including risk factors, med- these processes lead to fibrous cap rupture, expo- ication, symptoms, time of surgery, preoperative sure of tissue factor, atherothrombosis and clinical imaging and anthropometric and laboratory mea- manifestations [1, 2]. surements. Transcriptomic and genomic profiles have been generated by microarray and genotyping Embolization of ruptured plaques in the carotid chips, enabling multivariate analysis of gene bifurcation to the cerebral circulation can occur, expression patterns in relation to clinical parame- causing transient or permanent ischaemia. ters and genotype. Data from this biobank have Patients with high-grade carotid stenosis are been utilized previously, both in hypothesis-driven treated with stroke preventive interventions, but and hypothesis-independent studies [16–31]. In neither laboratory tests nor imaging have been this study, we postulated that phenotypes of clinically established for precise detection of unsta- patients with carotid atherosclerosis would corre- ble individuals or lesions [3]. A number of clinical late with specific gene expression patterns and we parameters influence the risk of stroke in patients analysed the global transcriptome in relationship with carotid stenosis. AS carotid disease is associ- to clinical features stratifying stroke risk. We have ated with an annual stroke risk of 1–3%, whereas S been able to identify novel molecular signatures patients with either transient ischaemic attack and pathways of plaque instability, validate (TIA) or minor stroke (MS) have a more than 10- established processes featuring late-stage fold increased risk [4]. In addition, it has been atherosclerosis as well as to highlight the temporal shown that TIA and MS confer a higher risk than dynamics and modulation of atherosclerosis by ocular symptoms [retinal TIA, amaurosis fugax; statin therapy. (AF)] [3]. Recurrent embolization and symptoms are most pronounced within the first 2 weeks after Materials and methods the index event [5, 6] and are thereafter gradually Human material reduced. Medical therapy with HMG CoA reductase inhibitors (statins) significantly reduces stroke Patients undergoing surgery for S or AS, high- risk, probably by improving plaque stability [7, 8]. grade (>50% North American Symptomatic Carotid Endarterectomy Trial, NASCET) [32] carotid steno- Large-scale transcriptomic analyses using sis at the Department of Vascular Surgery, Karolin- microarrays enable studies of expression patterns ska University Hospital, were consecutively to be performed for thousands of genes simultane- enrolled in the study. Informed consent was ously [9]. Although alternative technologies such obtained, and clinical data were recorded on as RNA sequencing are becoming available, admission. The following clinical parameters were microarrays remain powerful tools for investiga- selected for investigation in this study: presence tions of disease-related gene expression changes, and type of symptoms; statin treatment; and time particularly when combined with open-source soft- between last symptom and surgery. Symptoms of ware for high-throughput data exchange (e.g. Gene plaque instability were defined as TIA, MS and AF. Expression Omnibus (GEO) data sets and ArrayEx- TIA was defined as a transient episode of neuro- press) and a growing number of web-based pro- logical dysfunction, and MS as symptoms persist- grams for functional analysis. Previous attempts to ing >24 h with complete or nearly complete investigate global gene expression profiles in recovery. human atherosclerotic plaques [10–15] have been restricted by small sample sizes, the lack of Patients without qualifying symptoms within undiseased (nonatherosclerotic) vascular control 6 months prior to surgery were categorized as AS tissues or the inability to classify patients based on and indication for carotid endarterectomy based on 2 ª 2015 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine L. Perisic et al. Atherosclerosis transcriptome results from the Asymptomatic Carotid Surgery (a) Trial (ACST) [33]. Patients with atrial fibrillation and those who had suffered a major stroke were excluded from the study. Carotid endarterectomies (carotid plaques, CP) and peripheral blood samples were collected at surgery and retained within the BiKE. Plaques were divided transversally by the surgeon at the most stenotic part, and the proximal half of the lesion used for RNA preparation and the distal half fixed in 4% Zn-formaldehyde and pro- cessed for histology. RNA from tissues and periph- eral blood mononuclear cells (PBMCs) was analysed by gene expression microarrays, and gene expression in plaques was validated by
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