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Objective- Plaque macrophages are intricately involved in atherogenesis and plaque destabilization. We sought to identify functional pathways in human plaque macrophages that are differentially regulated in respect of (1) plaque stability and (2) lipid content. We hypothesized that differentially regulated macrophage gene sets would relate to genome-wide association study variants associated with risk of acute complications of atherosclerosis. Approach and Results- Forty patients underwent carotid magnetic resonance imaging for lipid quantification before endarterectomy. Carotid plaque macrophages were procured by laser capture microdissection from (1) lipid core and (2) cap region, in 12 recently symptomatic and 12 asymptomatic carotid plaques. Applying gene set enrichment analysis, a number of gene sets were found to selectively upregulate in symptomatic plaque macrophages, which corresponded to 7 functional pathways: inflammation, lipid metabolism, hypoxic response, cell proliferation, apoptosis, antigen presentation, and cellular energetics. Predicted upstream regulators included IL-1β, TNF-α, and NF-κB. In vivo lipid quantification by magnetic resonance imaging correlated most strongly with the upregulation of genes of the IFN/ STAT1 pathways. Cross-interrogation of gene set enrichment analysis and meta-analysis gene set enrichment of variant associations showed lipid metabolism pathways, driven by genes coding for APOE and ABCA1/G1 coincided with known risk-associated SNPs (single nucleotide polymorphisms) from genome-wide association studies. Conclusions- Macrophages from recently symptomatic carotid plaques show differential regulation of functional gene pathways. There were additional quantitative relationships between plaque lipid content and key gene sets. The data show a plausible mechanism by which known genome-wide association study risk variants for atherosclerotic complications could be linked to (1) a relevant cellular process, in (2) the key cell type of atherosclerosis, in (3) a human disease-relevant setting.

Original publication

DOI

10.1161/ATVBAHA.118.311209

Type

Journal article

Journal

Arterioscler Thromb Vasc Biol

Publication Date

11/2018

Volume

38

Pages

2718 - 2730

Keywords

atherosclerosis, genome-wide association study, laser capture microdissection, lipids, macrophages, magnetic resonance imaging, transcriptome, Adult, Aged, Aged, 80 and over, Carotid Arteries, Carotid Artery Diseases, Female, Gene Expression Profiling, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Macrophages, Magnetic Resonance Imaging, Male, Middle Aged, Phenotype, Plaque, Atherosclerotic, Principal Component Analysis, Rupture, Spontaneous, Transcriptome