ASXL1 mutations in clonal hematopoiesis accelerate aortic valve calcification
Large human cohort data and cell experiments show that ASXL1-driven clonal hematopoiesis worsens aortic valve hemodynamics and promotes calcification through inflammatory signaling.
medRxiv · 29 Sept · Small A, Xue L, Ito S et al.
In human participants from the UK Biobank and the ARIC study, researchers examined how clonal hematopoiesis of indeterminate potential relates to calcific aortic valve disease. Among 449,109 individuals in the UK Biobank, large clones and non-DNMT3A subtypes, including ASXL1, independently associated with incident aortic stenosis. In 1,963 ARIC participants with echocardiographic data, only ASXL1 mutations were associated with worse aortic valve hemodynamics. Mechanistic experiments using human ASXL1-mutant macrophage-like cells revealed increased AIM2 inflammasome activation and secreted factors that accelerated calcification in human valvular interstitial cells. Blocking interleukin-1 with anakinra or interleukin-6 with tocilizumab reduced this accelerated calcification in vitro.
Why it matters
Clonal hematopoiesis is a common feature of aging stem cells that drives chronic inflammation. Identifying specific gene drivers like ASXL1 helps explain how somatic mutations contribute to age-related cardiovascular deterioration.
Caveats
This study is a preprint that has not yet been peer-reviewed. The clinical conclusions rely on observational associations, and the mechanistic interventions were tested exclusively in cell culture models.
The paper
ASXL1-Mutant Clonal Hematopoiesis is Associated with Calcific Aortic Valve Disease and Promotes Valvular Calcification In Vitro
Small A, Xue L, Ito S et al.
medRxiv
doi.org/10.64898/2026.09.23.26363798