DOI: 10.1161/circ.148.suppl_1.14692 ISSN: 0009-7322

Abstract 14692: Clonal Hematopoiesis Driver Mutations Have Disparate Effects on Macrophage Cytokine Profiles and Only Modestly Drive Atherogenesis at Pathophysiological Levels

Paul Carter, Siddhartha Kar, Lauren Kitt, Nichola Figg, Pedro Quirós, Ang Zhou, Stephen Burgess, George Vassiliou, Peter Libby, Martin Bennett, Murray C Clarke
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Background: Clonal hematopoiesis (CH) is characterized by expansion of hematopoietic stem cells due to somatic mutations in leukemia-associated genes. CH is associated with increased mortality, attributed to cardiovascular disease (CVD) driven by increased IL-1β from clonal macrophages. However, different CH-driver mutations perturb diverse genes with distinct functions and reports of IL-1β release from mutant macrophages are discordant. Furthermore, directionality of the association between CH and CVD is not established.

Hypothesis: We hypothesized that mutations of common CH-driver genes have disparate effects on macrophage cytokine profiles and atherogenesis. We also hypothesized that atherosclerosis-driven systemic inflammation promotes clonal expansion.

Methods/Results: We characterised cytokine expression in LPS-treated murine bone marrow-derived macrophages (BMDMs) harboring CH-driver mutations ( Tet2 , Dnmt3a , or Jak2 ). Transcript level of Il1a , Il1b and Il6 was increased ~3-5 fold in Tet2 -/- and Dnmt3a -/- BMDMs, but only ~1.5-2 fold with heterozygotic loss, which mimics more closely patients with CH. Notably, Tet2 -/- BMDMs (but not Dnmt3a or Jak2 ) release more IL-1α/β, accompanied by increased Asc specks and caspase-1 activity, implying heightened NLRP3 inflammasome activation.

In murine chimera models of CH, Tet2 -/- and Tet2 +/- cells (but not Dnmt3a or Jak2 ), expand under the steady state. Clonal dynamics were unaffected by systemic inflammation via exogenous IL-1α, or high fat diet-induced atherogenesis in Ldlr -/- recipients.

Atherosclerotic plaques in murine CH models at 12 weeks are only mildly increased with heterozygotic Tet2, Dnmt3a, or Jak2 mutations (10-20%). Observational and Mendelian randomisation analyses of UK BioBank did not reveal bidirectional associations between CH and atherosclerosis.

Conclusions: We demonstrate augmented NLRP3 inflammasome activation in Tet2 -/- BMDMs and disparate effects of different CH mutations on cytokine profiles. We find no evidence for atherosclerosis or systemic inflammation driving clonal expansion. Thus, the pathogenesis of CH-driven disease should be treated as different entities for each mutation and likely involves overlapping or distinct mediators.

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