Leukocytes carrying Clonal Hematopoiesis of Indeterminate Potential (CHIP) Mutations invade Human Atherosclerotic Plaques.

von Scheidt, Moritz; Bauer, Sabine; Ma, Angela; Hao, Ke; Kessler, Thorsten; Vilne, Baiba; Wang, Ying; Hodonsky, Chani J; Ghosh, Saikat K B; Mokry, Michal; Gao, Hua; Kawai, Kenji; Sakamoto, Atsushi; Kaiser, Juliane; Bongiovanni, Dario; Fleig, Julia; Oldenbuettel, Lilith; Chen, Zhifen; Moggio, Aldo; Sager, Hendrik B; Hecker, Judith S; Bassermann, Florian; Maegdefessel, Lars; Miller, Clint L; Koenig, Wolfgang; Zeiher, Andreas M; Dimmeler, Stefanie; Graw, Matthias; Braun, Christian; Ruusalepp, Arno; Leeper, Nicholas J; Kovacic, Jason C; Björkegren, Johan L M; Schunkert, Heribert     «

von Scheidt, Moritz; Bauer, Sabine; Ma, Angela; Hao, Ke; Kessler, Thorsten; Vilne, Baiba; Wang, Ying; Hodonsky, Chani J; Ghosh, Saikat K B; Mokry, Michal; Gao, Hua; Kawai, Kenji; Sakamoto, Atsushi; Kaiser, Juliane; Bongiovanni, Dario; Fleig, Julia; Oldenbuettel, Lilith; Chen, Zhifen; Moggio, Aldo; Sager, Hendrik B; Hecker, Judith S; Bassermann, Florian; Maegdefessel, Lars; Miller, Clint L; Koenig, Wolfgang; Zeiher, Andreas M; Dimmeler, Stefanie; Graw, Matthias; Braun, Christian; Ruusalepp, Arno;...     »

BACKGROUND: Leukocyte 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. METHODS: CHIP 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 mutaFISH TM . Functional relevance of CHIP mutations was studied by RNAseq. RESULTS: DNAseq 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. MutaFISH TM visualized individual macrophages carrying DNMT3A CHIP 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 carrying TET2 mutations predominantly displayed upregulated inflammatory signaling whereas ASXL1 mutations showed stronger effects on metabolic pathways. CONCLUSIONS: Deep-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.      «

BACKGROUND: Leukocyte 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. METHODS: CHIP mutations in blood and tissues were identified by targeted deep-DNA-sequencing (DNAseq: coverage >3,000) and whole-genome-sequencing (WGS: covera...     »