Abstract 4140254: Sex Influences Effects on Atherosclerosis in
TET2
-related Clonal Hematopoiesis of Indeterminate Potential and on Interleukin-1β Inhibition in Mice
Authors: Vromman Amelie , Nakao Tetsushi , Fang Shi , Dreyfuss Jonathan , Pan Hui , Vellarikkal Shamsudheen , Janini Gomes Mariana , Carter Paul , Moscavitch Samuel , Uddin Md Mesbah , Cho So Mi , Xue Liying , Honigberg Michael , Paruchuri Kaavya , Koyama Satoshi , Zou Roger , Ganesh Shriienidhie , Zekavat Seyedeh , Vlasschaert Caitlyn , Sellar Rob , McConkey Marie , Yu Zhi , Tesmenitsky Yevgenia , Sausen Grasiele , Shvartz Eugenia , Wong Waihay , Ruvkun Victoria , Folco Eduardo , Sukhova Galina , Bick Alexander , Ebert Benjamin , Gupta Rajat , Natarajan Pradeep , Libby Peter 
Published: November 2024

Background:
Clonal hematopoiesis of indeterminate potential (CHIP) refers to somatic mutations in hematopoietic cells with a minimum allele fraction ≥ 2% without hematological disease. CHIP depends on age and increases the risk of coronary artery disease (CAD). In their 70s women’s prevalence of cardiovascular disease catches up to that of men. In Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) neutralizing interleukin-1β (IL-1β) in chronic CAD, subjects with
TET2
CHIP showed greater reduction of cardiovascular events. However, this substudy did not investigate sex.

Hypothesis:
We hypothesized that sex modifies the association between CHIP mutations and risk of CAD, and the effects of IL-1β inhibition in CHIP-related atherosclerosis in mice.

Methods:
Sex differences on the association of CAD and CHIP mutations were investigated using 2 cohorts: the UK and Mass General Brigham Biobanks. CHIP genes showing sex differences in human data were deleted in hematopoietic cells of female and male atherosclerosis-susceptible
Ldlr
-/-
mice. Mice consumed a 0.2% cholesterol high-fat diet with or without an anti-mouse IL-1β monoclonal antibody for 9 weeks. We assessed atherosclerosis by histology and performed mechanistic studies using single-cell RNA sequencing (scRNAseq) of atherosclerotic aortic arch and
in vitro
bone-marrow derived macrophages.

Results:
Women with
TET2
CHIP had larger hazard ratio for CAD than men in both biobanks. Overall CHIP and other mutations did not demonstrate sex differences in the association with CAD. In
Ldlr
-/-
mice deficient for
Tet2
in hematopoietic cells, IL-1β inhibition reduced atherosclerosis in female but not male mice. ScRNAseq revealed more inflammatory cells and more expression of inflammatory genes in hematopoietic
Tet2
-/-
females than in males. IL-1β inhibition limited these sex differences.
In vitro
experiments demonstrated that
Tet2
deficiency prevents the interaction between estrogen-receptor alpha and histone H3 controlling epigenetic regulation in mouse macrophages.

Conclusions:
Females with
TET2
CHIP have accentuated CAD risk and IL-1β blockade limits
Tet2
-augmented atherosclerosis in female but not male mice. These results highlight the importance of study of sex as a biological variable, uncover a new mechanism of
Tet2
CHIP on acceleration of atherosclerosis, and inform the design of trials refining allocation of anti-inflammatory therapies in
TET2
CHIP.