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Genetic modification of inflammation- and clonal hematopoiesis-associated cardiovascular risk

Yu, Zhi ; Fidler, Trevor P. ; Ruan, Yunfeng ; Vlasschaert, Caitlyn ; Nakao, Tetsushi ; Uddin, Md Mesbah ; Mack, Taralynn ; Niroula, Abhishek LU ; Brett Heimlich, J. and Zekavat, Seyedeh M. , et al. (2023) In Journal of Clinical Investigation 133(18).
Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with an increased risk of cardiovascular diseases (CVDs), putatively via inflammasome activation. We pursued an inflammatory gene modifier scan for CHIP-associated CVD risk among 424,651 UK Biobank participants. We identified CHIP using whole-exome sequencing data of blood DNA and modeled as a composite, considering all driver genes together, as well as separately for common drivers (DNMT3A, TET2, ASXL1, and JAK2). We developed predicted gene expression scores for 26 inflammasome-related genes and assessed how they modify CHIP-associated CVD risk. We identified IL1RAP as a potential key molecule for CHIP-associated CVD risk across genes and increased AIM2 gene... (More)

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with an increased risk of cardiovascular diseases (CVDs), putatively via inflammasome activation. We pursued an inflammatory gene modifier scan for CHIP-associated CVD risk among 424,651 UK Biobank participants. We identified CHIP using whole-exome sequencing data of blood DNA and modeled as a composite, considering all driver genes together, as well as separately for common drivers (DNMT3A, TET2, ASXL1, and JAK2). We developed predicted gene expression scores for 26 inflammasome-related genes and assessed how they modify CHIP-associated CVD risk. We identified IL1RAP as a potential key molecule for CHIP-associated CVD risk across genes and increased AIM2 gene expression leading to heightened JAK2- and ASXL1-associated CVD risk. We show that CRISPR-induced Asxl1-mutated murine macrophages had a particularly heightened inflammatory response to AIM2 agonism, associated with an increased DNA damage response, as well as increased IL-10 secretion, mirroring a CVDprotective effect of IL10 expression in ASXL1 CHIP. Our study supports the role of inflammasomes in CHIP-associated CVD and provides evidence to support gene-specific strategies to address CHIP-associated CVD risk.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Clinical Investigation
volume
133
issue
18
article number
e168597
publisher
The American Society for Clinical Investigation
external identifiers
  • pmid:37498674
  • scopus:85171393166
ISSN
0021-9738
DOI
10.1172/JCI168597
language
English
LU publication?
yes
id
6905ddbe-8b1e-43b5-9ae7-f31dbae12616
date added to LUP
2023-12-13 15:22:54
date last changed
2024-04-12 07:38:44
@article{6905ddbe-8b1e-43b5-9ae7-f31dbae12616,
  abstract     = {{<p>Clonal hematopoiesis of indeterminate potential (CHIP) is associated with an increased risk of cardiovascular diseases (CVDs), putatively via inflammasome activation. We pursued an inflammatory gene modifier scan for CHIP-associated CVD risk among 424,651 UK Biobank participants. We identified CHIP using whole-exome sequencing data of blood DNA and modeled as a composite, considering all driver genes together, as well as separately for common drivers (DNMT3A, TET2, ASXL1, and JAK2). We developed predicted gene expression scores for 26 inflammasome-related genes and assessed how they modify CHIP-associated CVD risk. We identified IL1RAP as a potential key molecule for CHIP-associated CVD risk across genes and increased AIM2 gene expression leading to heightened JAK2- and ASXL1-associated CVD risk. We show that CRISPR-induced Asxl1-mutated murine macrophages had a particularly heightened inflammatory response to AIM2 agonism, associated with an increased DNA damage response, as well as increased IL-10 secretion, mirroring a CVDprotective effect of IL10 expression in ASXL1 CHIP. Our study supports the role of inflammasomes in CHIP-associated CVD and provides evidence to support gene-specific strategies to address CHIP-associated CVD risk.</p>}},
  author       = {{Yu, Zhi and Fidler, Trevor P. and Ruan, Yunfeng and Vlasschaert, Caitlyn and Nakao, Tetsushi and Uddin, Md Mesbah and Mack, Taralynn and Niroula, Abhishek and Brett Heimlich, J. and Zekavat, Seyedeh M. and Gibson, Christopher J. and Griffin, Gabriel K. and Wang, Yuxuan and Peloso, Gina M. and Heard-Costa, Nancy and Levy, Daniel and Vasan, Ramachandran S. and Aguet, François and Ardlie, Kristin G. and Taylor, Kent D. and Rich, Stephen S. and Rotter, Jerome I. and Libby, Peter and Jaiswal, Siddhartha and Ebert, Benjamin L. and Bick, Alexander G. and Tall, Alan R. and Natarajan, Pradeep}},
  issn         = {{0021-9738}},
  language     = {{eng}},
  month        = {{09}},
  number       = {{18}},
  publisher    = {{The American Society for Clinical Investigation}},
  series       = {{Journal of Clinical Investigation}},
  title        = {{Genetic modification of inflammation- and clonal hematopoiesis-associated cardiovascular risk}},
  url          = {{http://dx.doi.org/10.1172/JCI168597}},
  doi          = {{10.1172/JCI168597}},
  volume       = {{133}},
  year         = {{2023}},
}