| Title: | Genetic modification of inflammation and clonal hematopoiesis-associated cardiovascular risk |
| Journal: | Journal of Clinical Investigation |
| Published: | 15 Sep 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/37498674/ |
| DOI: | https://doi.org/10.1172/jci168597 |
| URL: | http://www.jci.org/articles/view/168597/files/pdf |
Publication 9572
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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 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 CVD-protective 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>
28 Authors
- Zhi Yu
- Trevor P. Filder
- Yunfeng Ruan
- Caitlyn Vlasschaert
- Tetsushi Nakao
- Mesbah Uddin
- Taralynn Mack
- Abhishek Niroula
- J. Brett Heimlich
- Seyedeh M. Zekavat
- Christopher J. Gibson
- Gabriel K. Griffin
- Yuxuan Wang
- Gina M. Peloso
- Nancy Heard-Costa
- Daniel Levy
- Ramachandran S. Vasan
- François Aguet
- Kristin G. Ardlie
- Kent D. Taylor
- Stephen S. Rich
- Jerome I. Rotter
- Peter Libby
- Siddhartha Jaiswal
- Benjamin L. Ebert
- Alexander G. Bick
- Alan R. Tall
- Pradeep Natarajan
1 Application
| Application ID | Title |
|---|---|
| 7089 | Exome Sequencing of All Premature Coronary Artery Disease Participants in UK Biobank |
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