MechanismsHumansPreprint449,109 individualsCohort study

ASXL1-mutant clonal hematopoiesis links to aortic valve disease

In cohort data and cell models, ASXL1 mutations tracked with incident aortic stenosis and promoted valvular calcification that was reduced by IL-1 or IL-6 inhibition.

Figure 1. Multivariable-adjusted associations of CHIP and key CHIP subtypes with incident aortic stenosis in the UK Biobank Forest plot of hazard ratios for risk of incident aortic stenosis by CHIP status in… — Figure 1. Multivariable-adjusted associations of CHIP and key CHIP subtypes with incident aortic stenosis in the UK Biobank Forest plot of hazard ratios for risk of…Multivariable-adjusted associations of CHIP and key CHIP subtypes with incident aortic stenosis in the UK Biobank Forest plot of hazard ratios for risk of incident aortic stenosis by CHIP status in the UK Biobank.Small et al.

medRxiv2 Oct 2026, 21:27 BST

In an analysis of 449,109 participants in the UK Biobank, large clones and non-DNMT3A subtypes of clonal hematopoiesis of indeterminate potential—including ASXL1, TET2, and JAK2—were independently associated with incident aortic stenosis. Among 1,963 individuals in the Atherosclerosis Risk in Communities study, only ASXL1 mutations were associated with worse aortic valve hemodynamics. In cell culture experiments, conditioned media from human ASXL1-mutant macrophage-like cells accelerated calcification in human valvular interstitial cells. Proteomic profiling showed increased inflammatory proteins and AIM2 inflammasome activation in these mutant cells. Inhibiting interleukin-1 with anakinra or interleukin-6 with tocilizumab reduced the accelerated calcification in cultured valve cells.

Why it matters

Clonal hematopoiesis is an age-acquired condition that increases cardiovascular risk through inflammatory signaling. These findings suggest that specific mutation subtypes may contribute to distinct mechanisms of age-related valvular disease that could be targeted pharmacologically.

Caveats

The clinical findings are observational and cannot establish causality, while the mechanistic evaluations relied on cultured cell lines rather than in vivo models. The study is also a preprint that has not yet undergone peer review.