Leukocytes carrying Clonal Hematopoiesis of Indeterminate Potential (CHIP) Mutations invade Human Atherosclerotic Plaques.
Leukocytes carrying Clonal Hematopoiesis of Indeterminate Potential (CHIP) Mutations invade Human Atherosclerotic Plaques.
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携带不确定电位克隆造血 (CHIP) 突变的白细胞侵入人类动脉粥样硬化斑块。
DOI：
10.1101/2023.07.22.23292754
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Oldenb
中科院分区：
文献类型：
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作者：
vonScheidt,Moritz;Bauer,Sabine;Ma,Angela;Hao,Ke;Kessler,Thorsten;Vilne,Baiba;Wang,Ying;Hodonsky,ChaniJ;Ghosh,SaikatKB;Mokry,Michal;Gao,Hua;Kawai,Kenji;Sakamoto,Atsushi;Kaiser,Juliane;Bongiovanni,Dario;Fleig,Julia;Oldenb
来自克隆造血潜能不确定（CHIP）的白细胞祖细胞与心血管事件的增加有关。然而，CHIP在冠状动脉疾病（CAD）中的患病率和功能相关性尚不清楚，并且在人类动脉粥样硬化斑块中尚未检测到受CHIP影响的细胞。方法采用靶向深度dna测序（DNAseq：覆盖> - 3000）和全基因组测序（WGS：覆盖> - 35）对血液和组织中的schip突变进行鉴定。通过mutaFISHTM观察人类动脉粥样硬化斑块中chip突变的白细胞。通过RNAseq研究CHIP突变的功能相关性。结果来自慕尼黑心血管研究生物银行（MISSION）的540例已故CAD患者的全血dna检测发现253例（46.9%）CHIP突变携带者（平均年龄78.3岁）。在25个组织DNA突变携带者中，18个在心肌、动脉粥样硬化冠状动脉和颈动脉上检测到相同的CHIP突变。mutafishm可视化人类动脉粥样硬化斑块中携带dnmt3achip突变的单个巨噬细胞。通过WGS研究来自Stockholm-Tartu动脉粥样硬化反向网络工程任务（STARNET; n=941）的单核细胞来源的巨噬细胞发现14.2%的CHIP突变（平均年龄67.1岁）。这些巨噬细胞的RNAseq显示CHIP突变携带者的表达模式与非携带者有很大不同。此外，模式因潜在突变而异，例如，携带te2突变的人主要表现出炎症信号上调，而asxl1突变对代谢途径的影响更大。结论深dna测序显示冠心病患者全血中CHIP突变发生率较高。chip影响的白细胞侵入人冠状动脉斑块。从chip患者巨噬细胞中获得的RNAseq数据表明，促动脉粥样硬化信号因潜在突变而异。需要进一步的研究来了解受CHIP突变影响的特定途径是否可以针对个体化治疗。
BackgroundLeukocyte progenitors derived from clonal hematopoiesis of undetermined potential (CHIP) are associated with increased cardiovascular events. However, the prevalence and functional relevance of CHIP in coronary artery disease (CAD) are unclear, and cells affected by CHIP have not been detected in human atherosclerotic plaques.MethodsCHIP mutations in blood and tissues were identified by targeted deep-DNA-sequencing (DNAseq: coverage >3,000) and whole-genome-sequencing (WGS: coverage >35). CHIP-mutated leukocytes were visualized in human atherosclerotic plaques by mutaFISHTM. Functional relevance of CHIP mutations was studied by RNAseq.ResultsDNAseq of whole blood from 540 deceased CAD patients of the Munich cardIovaScular StudIes biObaNk (MISSION) identified 253 (46.9%) CHIP mutation carriers (mean age 78.3 years). DNAseq on myocardium, atherosclerotic coronary and carotid arteries detected identical CHIP mutations in 18 out of 25 mutation carriers in tissue DNA. MutaFISHTMvisualized individual macrophages carryingDNMT3ACHIP mutations in human atherosclerotic plaques. Studying monocyte-derived macrophages from Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task (STARNET; n=941) by WGS revealed CHIP mutations in 14.2% (mean age 67.1 years). RNAseq of these macrophages revealed that expression patterns in CHIP mutation carriers differed substantially from those of non-carriers. Moreover, patterns were different depending on the underlying mutations, e.g. those carryingTET2mutations predominantly displayed upregulated inflammatory signaling whereasASXL1mutations showed stronger effects on metabolic pathways.ConclusionsDeep-DNA-sequencing reveals a high prevalence of CHIP mutations in whole blood of CAD patients. CHIP-affected leukocytes invade plaques in human coronary arteries. RNAseq data obtained from macrophages of CHIP-affected patients suggest that pro-atherosclerotic signaling differs depending on the underlying mutations. Further studies are necessary to understand whether specific pathways affected by CHIP mutations may be targeted for personalized treatment.