Differential Gene Expression in Macrophages From Human Atherosclerotic Plaques Shows Convergence on Pathways Implicated by Genome-Wide Association Study Risk Variants.
Differential Gene Expression in Macrophages From Human Atherosclerotic Plaques Shows Convergence on Pathways Implicated by Genome-Wide Association Study Risk Variants.
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DOI：
10.1161/atvbaha.118.311209
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发表时间：
2018-11
期刊：
影响因子：
--
通讯作者：
Choudhury RP
中科院分区：
文献类型：
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作者：
Chai JT;Ruparelia N;Goel A;Kyriakou T;Biasiolli L;Edgar L;Handa A;Farrall M;Watkins H;Choudhury RP
补充数字内容可在文本中找到。斑块巨噬细胞复杂地参与动脉粥样硬化形成和斑块不稳定。我们试图确定人类斑块巨噬细胞中的功能途径，这些途径在（1）斑块稳定性和（2）脂质含量方面受到差异调节。我们假设差异调节的巨噬细胞基因组与动脉粥样硬化急性并发症风险相关的全基因组关联研究变异有关。40例患者在动脉内膜切除术前接受颈动脉磁共振成像进行脂质定量。采用激光捕获显微切割技术，从12例近期有症状和12例无症状颈动脉斑块的（1）脂质核心和（2）帽区获得颈动脉斑块巨噬细胞。应用基因集富集分析，发现许多基因集在有症状的斑块巨噬细胞中选择性上调，其对应于7个功能通路：炎症、脂质代谢、缺氧反应、细胞增殖、凋亡、抗原呈递和细胞能量学。预测的上游调节因子包括IL-1β、TNF-α和NF-κB。通过磁共振成像进行的体内脂质定量与IFN/STAT 1途径基因的上调最密切相关。交叉询问基因集富集分析和荟萃分析基因集富集变异关联显示，由编码APOE和ABCA 1/G1的基因驱动的脂质代谢途径与全基因组关联研究中已知的风险相关SNP（单核苷酸多态性）一致。最近有症状的颈动脉斑块中的巨噬细胞显示功能性基因通路的差异调节。斑块脂质含量和关键基因集之间存在额外的定量关系。这些数据显示了一种合理的机制，通过这种机制，已知的动脉粥样硬化并发症的全基因组关联研究风险变异可能与（1）相关的细胞过程，（2）动脉粥样硬化的关键细胞类型，（3）人类疾病相关的环境有关。
Supplemental Digital Content is available in the text. 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. 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. 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.