What does this research mean for the field?

ASXL1 CHIP is an independent risk factor for calcific aortic valve disease, associated with incident aortic stenosis (HR 1.52) and increased aortic valve gradients. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.CHALLENGES_CONSENSUS.

What question did this study set out to answer?

This research evaluates the role of clonal hematopoiesis of indeterminate potential (CHIP) as a risk factor for calcific aortic valve disease (CAVD).

February 8, 2026

ASXL1 CHIP is a risk factor for calcific aortic valve disease

Key Result

ASXL1 CHIP increased risk of incident aortic stenosis (HR 1.52) and was linked to higher aortic valve gradients, indicating it as an independent CAVD risk factor.

Key Points

This research evaluates the role of clonal hematopoiesis of indeterminate potential (CHIP) as a risk factor for calcific aortic valve disease (CAVD).
Examined the association of CHIP with CAVD using UK Biobank and ARIC Study data.
Determined CHIP presence using whole exome sequencing and variant allele fractions (VAF).
Analyzed incident aortic stenosis through claims-based definitions and aortic valve hemodynamics via echocardiography.
Utilized Cox models and linear regression for statistical analysis.
Among 454,327 individuals in the UKB, 3,444 developed incident aortic stenosis.
Any CHIP found in 15,426 individuals; ASXL1 CHIP associated with higher incident aortic stenosis risk (HR 1.52).
In ARIC, ASXL1 CHIP correlated with increased aortic valve mean gradient and peak velocity.
These findings suggest ASXL1 CHIP is an independent risk factor for CAVD.

Structured PICO

Does the presence of CHIP increase the risk of incident calcific aortic valve disease in the general population?

Population

454,327 individuals with whole exome sequencing in the UK Biobank (mean age 57 years, 46% male) and 1,963 individuals with whole exome sequencing and echocardiographic data in the Atherosclerosis Risk in Communities (ARIC) Study (mean age 74 years, 42% male).

Intervention

Presence of any clonal hematopoiesis of indeterminate potential (CHIP) (variant allele fraction [VAF] ≥2%), large CHIP (VAF ≥10%), and individual CHIP driver mutations (DNMT3A, TET2, ASXL1, and JAK2) ascertained using whole exome sequencing.

Comparator

Absence of CHIP.

Outcome

Incident aortic stenosis (AS) in the UK Biobank and aortic valve hemodynamics (mean gradient and peak velocity) ascertained by echocardiography in ARIC.hard clinical

ASXL1 CHIP is an independent risk factor for the development of calcific aortic valve disease, highlighting a novel genetic and hematologic link to aortic stenosis.

Main Result

Absolute Event Rate: 0% vs 0%

Abstract

Abstract Background Calcific aortic valve disease (CAVD) is a progressive fibrocalcific pathology of the aortic valve resulting in aortic stenosis (AS), the most common valvular heart disease. Clonal hematopoiesis of indeterminate potential (CHIP) is a condition characterized by the proliferation of blood cell clones with select advantageous somatic mutations. CHIP is an independent risk factor for all-cause mortality and atherosclerotic cardiovascular disease. However, whether CHIP is a risk factor for the development of CAVD is currently unknown. Purpose To evaluate whether CHIP is an independent risk factor for CAVD. Methods We tested the association between CHIP and CAVD using data from the UK Biobank (UKB) and the Atherosclerosis Risk in Communities (ARIC) Study. Key exposures were the presence of any CHIP (defined as a variant allele fraction VAF ≥2%), large CHIP (VAF ≥10%), and individual CHIP driver mutations (e.g., DNMT3A, TET2, ASXL1, and JAK2) at baseline in the UKB and at visit 5 in ARIC, ascertained using whole exome sequencing (WES). Incident AS was determined in the UK Biobank using a previously validated claims-based definition. Aortic valve hemodynamics (mean gradient and peak velocity) ascertained by echocardiography at ARIC visit 7 were examined as log-transformed continuous measures. Cox models were fitted to test the association of CHIP with incident AS in the UKB. Linear regression was used to test the association of CHIP with aortic valve hemodynamics in ARIC. All models were adjusted for age at sequencing, sex, race, type 2 diabetes, body mass index, smoking, and chronic kidney disease. Results Among 454,327 individuals with WES in the UKB (mean age 57 years, 46% male sex), 3,444 (0.8%) individuals developed incident AS. Any CHIP was identified in 15,426 (3.4%) individuals. The most common CHIP clones were DNMT3A (9,570 2.1% individuals), TET2 (2,211 0.5% individuals), and ASXL1 (1,710 0.4% individuals). Among 1,963 individuals with WES and visit 7 echocardiographic data in ARIC (mean age 74 years, 42% male sex), any CHIP was identified in 430 (21.9%) individuals. The most common CHIP clones were DNMT3A (226 11.5% individuals), TET2 (80 4.1% individuals), and ASXL1 (24 1.2% individuals). In adjusted analysis in the UKB, large CHIP, TET2 CHIP, ASXL1 CHIP, and JAK2 CHIP were each associated with incident AS (large CHIP: HR 1.22 95% CI 1.02-1.45, P=0.03; ASXL1: HR 1.52 1.10-2.02, P=0.02; TET2: HR 1.41 1.03-1.95, P=0.03; JAK2: HR 3.39 1.61-7.11, P=0.002). Associations were robust after further adjustment for CAD. In fully adjusted analyses in ARIC, ASXL1, but not other CHIP subtypes, was associated with increased aortic valve mean gradient (P=0.03) and peak velocity (P=0.04). Conclusion ASXL1 CHIP was associated with incident AS in the UKB and higher aortic valve gradients in ARIC. These data suggest that ASXL1 CHIP is an independent risk factor for the development of CAVD.

Mark Helpful

Bookmark

Relay