# Common clonal hematopoiesis driver mutations have disparate effects on macrophage cytokines, clonal expansion, and atherogenesis

## TL;DR

Common blood mutations linked to disease risk have different effects on immune cells and artery disease, depending on the mutation and sex.

## Contribution

Shows that CHIP mutations have distinct effects on inflammation, cell expansion, and atherosclerosis, with sex-dependent differences.

## Key findings

- Tet2 mutations increase macrophage cytokines and expand clones, while Dnmt3a mutations decrease them.
- Atherosclerosis risk varies by mutation and sex, with no common mechanism across CHIP mutations.
- Clonal expansion is not driven by systemic inflammation but is influenced by hyperlipidemia in Tet2 mutants.

## Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is the expansion of blood stem cells and progeny after somatic mutation. CHIP associates with increased cardiovascular disease (CVD), with inflammation from macrophages a proposed common effector. However, mouse CHIP studies are discordant for clonal expansion and inflammation. Similarly, directionality of association between CHIP and CVD remains debated. We investigated effects of 3 CHIP mutations on macrophage cytokines, clonal expansion, and atherosclerosis in parallel. We found that cytokine release and inflammasome activation are increased by Tet2 mutation but decreased by Dnmt3a. However, Jak2 mutant macrophages produced equivalent cytokine as WT. In mice, Tet2 mutants clonally expanded, but Dnmt3a and Jak2 mutants did not. Expansion was unaffected by systemic inflammation, while hyperlipidemia expanded Tet2–/– cells but not mono-allelic mutants. Similarly, human Mendelian randomization showed no effect of serum cytokines or CVD on CHIP risk. Experimental atherosclerosis was increased in females with Tet2 and males with Jak2, but it was unchanged with Dnmt3a mutations. Together, common CHIP mutations have disparate effects on macrophage cytokines and clonal expansion, and they have sex-dependent effects on atherogenesis, suggesting a common mechanism across CHIP is unlikely. Thus, CHIP mutations differ in pathophysiology and clinical sequelae across sexes and should be treated as different entities.

CHIP associates with diseases. We find CHIP mutations disparately alter cytokines, clonal expansion, and sex-dependently effects atherosclerosis - suggesting a common mechanism across CHIP is unlikely.