# Mechanisms and Modulation of Accelerated Atherosclerosis in Clonal Hematopoiesis

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $646,417

## Abstract

Project Summary/Abstract
With age, humans can accumulate leukocyte clones in blood that arise from somatic mutations in bone marrow
stem cells that enhance expansion: clonal hematopoiesis of indeterminate potential (CHIP). Mutations in
DNMT3A and TET2 account for the plurality of these clones. CHIP confers highly elevated cardiovascular (CV)
risk, independent of traditional risk factors. We have found accelerated atherogenesis and the involvement of
IL-1 and IL-6 in mice with myeloid loss of Tet2 or Dnmt3a function and that genetically reduced IL-6 signaling
abrogates the elevated CV risk in humans with DNMT3A or TET2 CHIP. Analyses of our CANTOS trial showed
greater efficacy of IL-1β inhibition in humans with DNMT3A or TET2 CHIP. These results point the way to a
genotype-directed allocation of therapy, an approach that has transformed oncology but remains aspirational in
atherosclerosis. The roles of classical vs. trans IL-6 signaling in atherothrombosis requires further study due to
conflicting evidence. Specific aim 1 will test the hypothesis that atherosclerotic mice that mimic CHIP due to
myeloid deficiency in Dnmt3a treated with an antibody that interrupts global IL-6 signaling by neutralizing IL-6
receptor α (IL-6r, CD126) have decreased atherosclerosis and inflammation within the lesions, blood and other
organs as gauged in part by single-cell RNA sequencing (scRNA-seq). We further hypothesize that IL-6r
inhibition will limit expansion of the mutant clone. Specific aim 2 will probe the role of classical vs. trans IL-6
signaling in myeloid cells in accelerated atherogenesis in CHIP using Il6rflox/flox/Lyz2-Cre mice bone marrow
chimeric LDLR-/- mice (to block leukocyte classical signaling), and administration of a gp130-IgG1-Fc chimeric
protein (to block trans signaling) using similar procedures and endpoints. The results will illuminate the
controversy and unsettled science regarding the contributions of classical and trans IL-6 signaling to
atherogenesis. Specific aim 3. Our preliminary experiments show that female myeloidTet2-/-Ldlr-/- mice have
greater acceleration of atherogenesis than Tet2+/+ Ldlr-/- male mice and, unlike their male counterparts, show
reduced atherogenesis with IL-1β neutralization. We will localize where this sex difference operates in the
inflammasome–IL-1β–IL-6 pathway, and test the hypothesis that female Dnmt3a-/-Ldlr-/- mice have greater
response to IL-6r inhibition than males. We will probe mechanisms by gonadal ablation experiments and by
analysis of scRNA-seq data, which in preliminary data shows IL-1β expression in resident macrophages cells
from atheroma from Tet2-/- females but not males. This work will deepen understanding of the mechanisms of
accelerated atherosclerosis in CHIP. Our new pilot clinical data show that an anti-IL-6 antibody can mute
inflammation in humans. Thus, the work proposed here will provide an indispensable step toward validating
and furnishing the fundamental basis of an immediately ...

## Key facts

- **NIH application ID:** 10418315
- **Project number:** 1R01HL163099-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Peter Libby
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $646,417
- **Award type:** 1
- **Project period:** 2022-04-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10418315

## Citation

> US National Institutes of Health, RePORTER application 10418315, Mechanisms and Modulation of Accelerated Atherosclerosis in Clonal Hematopoiesis (1R01HL163099-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10418315. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*