Atherosclerosis 204 (2009) e15–e20 Contents lists available at ScienceDirect Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis Expression of chemokine (C–C motif) ligand 18 in human macrophages and atherosclerotic plaques Daniel A. Hägg a,∗ , Fredrik J. Olson a , Josefin Kjelldahl a , Margareta Jernås a , Dag S. Thelle b , Lena M.S. Carlsson a , Björn Fagerberg a , Per-Arne Svensson a a Center of Metabolic and Cardiovascular Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Göteborg, Vita Stråket 15, 41345 Göteborg, Sweden b Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway article info Article history: Received 15 August 2008 Received in revised form 24 September 2008 Accepted 7 October 2008 Available online 1 November 2008 Keywords: Atherosclerosis Endarterectomy Genomics CCL18 Macrophages abstract Objective: Using gene expression profiling, we aimed to identify genes that are predominantly expressed in human carotid atherosclerotic plaques. Such genes may be important in atherogenesis and patho- physiology of the plaque, and genes that encode for secreted proteins may be potential biomarkers for atherosclerosis and cardiovascular disease. Methods: DNA microarray generated expression profiles of human carotid atherosclerotic plaques were compared to expression profiles of 80 different human tissues and cell types, to identify plaque-specific genes. Results: We identified the chemokine (C–C motif) ligand 18 (CCL18) as predominantly expressed in human carotid plaque. Immunohistochemistry showed that CCL18 protein was localized to a subset of macrophages in carotid plaques. Monocyte-derived macrophages from subjects with atherosclerosis had threefold higher expression of CCL18 than macrophages from control subjects (p = 0.012). Subjects with A/G genotype of the rs2015086 SNP in the promoter region of the CCL18 gene had threefold higher macrophage expression of CCL18 than subjects with A/A genotype (p = 0.049), but we found no asso- ciation of this SNP with an increased risk of coronary heart disease. We also compared serum levels of CCL18 from subjects with symptomatic carotid artery disease with control subjects. There were no differ- ences in serum levels of CCL18 between the two groups, however CCL18 correlated with measurements of adiposity. Conclusion: CCL18 is predominantly expressed in human atherosclerotic plaques and may participate in the atherosclerotic plaque formation. © 2008 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Global gene expression analyses has emerged as a powerful tool to identify candidate genes and disease mechanisms for car- diovascular disease [1]. However, several factors limit its use to identify genes that are important in the formation of the atheroscle- rotic plaque. For example, the plaque consists of several cell types at different stages of development, meaning that an altered gene expression could be due to altered cell composition of the plaque. Furthermore, arteries from various locations in the body have dif- ferent phenotypes, which makes it difficult to find a relevant control tissue for expression profile comparisons [2]. In the past few years, a number of studies using DNA microarray of atherosclerotic plaques ∗ Corresponding author. Tel.: +46 313423604; fax: +46 31418527. E-mail address: daniel.hagg@medic.gu.se (D.A. Hägg). have been published [3–7]. However, they have mainly focused on differences between healthy and atherosclerotic arteries or stable and unstable plaques. Our perspective has been to view the carotid plaque as a unique tissue and focused on identifying what sep- arates this tissue from other major tissues and cell types of the body. We have developed a strategy to identify genes predomi- nantly expressed in a certain cell type or tissue [8]. By comparing the expression profiles of the carotid plaques with expression pro- files of 80 different tissues and cell lines, we were able to identify genes with their predominant expression site in carotid plaques. Using this approach no normal artery control is needed, eliminating the problem of selecting a valid control tissue. Such plaque-specific genes may be important in atherogenesis and pathophysiology of the plaque. Also, plaque-specific genes that encode for secreted proteins might be suitable as biomarkers for atherosclerosis. Applying this strategy, we identified the chemokine (C–C motif) ligand 18 (CCL18) as predominantly expressed in carotid plaque. 0021-9150/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2008.10.010