Genetic modification of inflammation- and clonal hematopoiesis–associated cardiovascular risk
Zhi Yu, Trevor P. Fidler, Yunfeng Ruan, Caitlyn Vlasschaert, Tetsushi Nakao, Md 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
Zhi Yu, Trevor P. Fidler, Yunfeng Ruan, Caitlyn Vlasschaert, Tetsushi Nakao, Md 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
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Research Article Cardiology Genetics

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

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.

Authors

Zhi Yu, Trevor P. Fidler, Yunfeng Ruan, Caitlyn Vlasschaert, Tetsushi Nakao, Md 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

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Figure 7

Asxl1 mutations and atherosclerosis.

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Asxl1 mutations and atherosclerosis. Mice receiving transplants of chim...
Mice receiving transplants of chimeric mixtures of bone with nontargeting guide RNAs (control) and Asxl1-G623* guides. (A) Terminal serum cholesterol. Complete blood cell counts at the end of WTD feeding for (B) white blood cells, (C) lymphocytes, (D) monocytes, and (E) neutrophils. (F) Spleen weight. %CD45.2+ mutated cells in blood (G) lymphocytes, (H) monocytes, and (I) neutrophils. (J) Representative images of H&E-stained aortic root lesions, and (K) quantification of lesion area and (L) necrotic core area. Data are mean ± SEM. Students t test, A–F, K, and L. Two-way ANOVA followed by Tukey’s post hoc test, G–I. Magnification in J is ×10.