Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

TP53-mediated clonal hematopoiesis confers increased risk for incident atherosclerotic disease

Zekavat, Seyedeh M. ; Viana-Huete, Vanesa ; Matesanz, Nuria ; Jorshery, Saman Doroodgar ; Zuriaga, María A. ; Uddin, Md Mesbah ; Trinder, Mark ; Paruchuri, Kaavya ; Zorita, Virginia and Ferrer-Pérez, Alba , et al. (2023) In Nature Cardiovascular Research 2(2). p.144-158
Abstract

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 the 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... (More)

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 the 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 after 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.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Cardiovascular Research
volume
2
issue
2
pages
15 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85165191597
  • pmid:36949957
ISSN
2731-0590
DOI
10.1038/s44161-022-00206-6
language
English
LU publication?
yes
id
735c1d2f-e8cb-442f-b84b-606346b78f69
date added to LUP
2023-09-22 14:15:56
date last changed
2024-07-12 09:07:06
@article{735c1d2f-e8cb-442f-b84b-606346b78f69,
  abstract     = {{<p>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 the 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 <sup>−/−</sup> chimeric mice carrying 20% p53-deficient hematopoietic cells. The chimeric mice were analyzed 13 weeks after 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.</p>}},
  author       = {{Zekavat, Seyedeh M. and Viana-Huete, Vanesa and Matesanz, Nuria and Jorshery, Saman Doroodgar and Zuriaga, María A. and Uddin, Md Mesbah and Trinder, Mark and Paruchuri, Kaavya and Zorita, Virginia and Ferrer-Pérez, Alba and Amorós-Pérez, Marta and Kunderfranco, Paolo and Carriero, Roberta and Greco, Carolina M. and Aroca-Crevillen, Alejandra and Hidalgo, Andrés and Damrauer, Scott M. and Ballantyne, Christie M. and Niroula, Abhishek and Gibson, Christopher J. and Pirruccello, James and Griffin, Gabriel and Ebert, Benjamin L. and Libby, Peter and Fuster, Valentín and Zhao, Hongyu and Ghassemi, Marzyeh and Natarajan, Pradeep and Bick, Alexander G. and Fuster, José J. and Klarin, Derek}},
  issn         = {{2731-0590}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{144--158}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Cardiovascular Research}},
  title        = {{TP53-mediated clonal hematopoiesis confers increased risk for incident atherosclerotic disease}},
  url          = {{http://dx.doi.org/10.1038/s44161-022-00206-6}},
  doi          = {{10.1038/s44161-022-00206-6}},
  volume       = {{2}},
  year         = {{2023}},
}