TP53-mediated clonal hematopoiesis confers increased risk for incident atherosclerotic disease
Somatic mutations in blood indicative of clonal hematopoiesis of indeterminate potential (CHIP) are associated with an increased risk of hematologic malignancy, coronary artery disease, and all-cause mortality. Here we analyze the relation between CHIP status and incident peripheral artery disease (PAD) and atherosclerosis, using whole-exome sequencing and clinical data from the UK Biobank and Mass General Brigham Biobank. CHIP associated with incident PAD and atherosclerotic disease across multiple beds, with increased risk among individuals with CHIP driven by mutation in DNA Damage Repair (DDR) genes such as TP53 and PPM1D. To model the effects of DDR-induced CHIP on atherosclerosis, we used a competitive bone marrow transplantation strategy, and generated atherosclerosis-prone Ldlr-/- chimeric mice carrying 20% p53-deficient hematopoietic cells. The chimeric mice were analyzed 13-weeks post-grafting and showed increased aortic plaque size and accumulation of macrophages within the plaque, driven by increased proliferation of p53-deficient plaque macrophages. In summary, our findings highlight the role of CHIP as a broad driver of atherosclerosis across the entire arterial system beyond the coronary arteries, and provide genetic and experimental support for a direct causal contribution of TP53-mutant CHIP to atherosclerosis.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:2 |
|---|---|
| Enthalten in: |
Nature cardiovascular research - 2(2023) vom: 16. Jan., Seite 144-158 |
| Sprache: |
Englisch |
|---|
| Links: |
|---|
| Themen: |
Atherosclerosis |
|---|
| Anmerkungen: |
Date Revised 21.10.2023 published: Print Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.1038/s44161-022-00206-6 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM354551493 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM354551493 | ||
| 003 | DE-627 | ||
| 005 | 20231226062452.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s44161-022-00206-6 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1181.xml |
| 035 | |a (DE-627)NLM354551493 | ||
| 035 | |a (NLM)36949957 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Zekavat, Seyedeh M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a TP53-mediated clonal hematopoiesis confers increased risk for incident atherosclerotic disease |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 21.10.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a Somatic mutations in blood indicative of clonal hematopoiesis of indeterminate potential (CHIP) are associated with an increased risk of hematologic malignancy, coronary artery disease, and all-cause mortality. Here we analyze the relation between CHIP status and incident peripheral artery disease (PAD) and atherosclerosis, using whole-exome sequencing and clinical data from the UK Biobank and Mass General Brigham Biobank. CHIP associated with incident PAD and atherosclerotic disease across multiple beds, with increased risk among individuals with CHIP driven by mutation in DNA Damage Repair (DDR) genes such as TP53 and PPM1D. To model the effects of DDR-induced CHIP on atherosclerosis, we used a competitive bone marrow transplantation strategy, and generated atherosclerosis-prone Ldlr-/- chimeric mice carrying 20% p53-deficient hematopoietic cells. The chimeric mice were analyzed 13-weeks post-grafting and showed increased aortic plaque size and accumulation of macrophages within the plaque, driven by increased proliferation of p53-deficient plaque macrophages. In summary, our findings highlight the role of CHIP as a broad driver of atherosclerosis across the entire arterial system beyond the coronary arteries, and provide genetic and experimental support for a direct causal contribution of TP53-mutant CHIP to atherosclerosis | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a atherosclerosis | |
| 650 | 4 | |a clonal hematopoiesis | |
| 650 | 4 | |a sequencing | |
| 650 | 4 | |a somatic | |
| 700 | 1 | |a Viana-Huete, Vanesa |e verfasserin |4 aut | |
| 700 | 1 | |a Matesanz, Nuria |e verfasserin |4 aut | |
| 700 | 1 | |a Jorshery, Saman Doroodgar |e verfasserin |4 aut | |
| 700 | 1 | |a Zuriaga, María A |e verfasserin |4 aut | |
| 700 | 1 | |a Uddin, Md Mesbah |e verfasserin |4 aut | |
| 700 | 1 | |a Trinder, Mark |e verfasserin |4 aut | |
| 700 | 1 | |a Paruchuri, Kaavya |e verfasserin |4 aut | |
| 700 | 1 | |a Zorita, Virginia |e verfasserin |4 aut | |
| 700 | 1 | |a Ferrer-Pérez, Alba |e verfasserin |4 aut | |
| 700 | 1 | |a Amorós-Pérez, Marta |e verfasserin |4 aut | |
| 700 | 1 | |a Kunderfranco, Paolo |e verfasserin |4 aut | |
| 700 | 1 | |a Carriero, Roberta |e verfasserin |4 aut | |
| 700 | 1 | |a Greco, Carolina M |e verfasserin |4 aut | |
| 700 | 1 | |a Aroca-Crevillen, Alejandra |e verfasserin |4 aut | |
| 700 | 1 | |a Hidalgo, Andrés |e verfasserin |4 aut | |
| 700 | 1 | |a Damrauer, Scott M |e verfasserin |4 aut | |
| 700 | 1 | |a Ballantyne, Christie M |e verfasserin |4 aut | |
| 700 | 1 | |a Niroula, Abhishek |e verfasserin |4 aut | |
| 700 | 1 | |a Gibson, Christopher J |e verfasserin |4 aut | |
| 700 | 1 | |a Pirruccello, James |e verfasserin |4 aut | |
| 700 | 1 | |a Griffin, Gabriel |e verfasserin |4 aut | |
| 700 | 1 | |a Ebert, Benjamin L |e verfasserin |4 aut | |
| 700 | 1 | |a Libby, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Fuster, Valentín |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Hongyu |e verfasserin |4 aut | |
| 700 | 1 | |a Ghassemi, Marzyeh |e verfasserin |4 aut | |
| 700 | 1 | |a Natarajan, Pradeep |e verfasserin |4 aut | |
| 700 | 1 | |a Bick, Alexander G |e verfasserin |4 aut | |
| 700 | 1 | |a Fuster, José J |e verfasserin |4 aut | |
| 700 | 1 | |a Klarin, Derek |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Nature cardiovascular research |d 2022 |g 2(2023) vom: 16. Jan., Seite 144-158 |w (DE-627)NLM335717950 |x 2731-0590 |7 nnns |
| 773 | 1 | 8 | |g volume:2 |g year:2023 |g day:16 |g month:01 |g pages:144-158 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s44161-022-00206-6 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 2 |j 2023 |b 16 |c 01 |h 144-158 | ||