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

J Clin Invest. 2023 Sep 15;133(18):e168597. doi: 10.1172/JCI168597.


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.

Keywords: Cardiology; Cardiovascular disease; Genetics; Mouse models; Population genetics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiovascular Diseases* / genetics
  • Clonal Hematopoiesis / genetics
  • Heart Disease Risk Factors
  • Hematopoiesis / genetics
  • Humans
  • Inflammasomes / genetics
  • Inflammation / complications
  • Inflammation / genetics
  • Mice
  • Mutation
  • Risk Factors


  • Inflammasomes