Related Experiment Video
Updated: Jan 11, 2026
Bone Marrow Transplantation Procedures in Mice to Study Clonal Hematopoiesis
Published on: May 26, 2021
Clonal Hematopoiesis and Incident Heart Failure
Spencer Flynn1,2,3, Art Schuermans1,4, Md Mesbah Uddin1
1Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
Insights
Clonal hematopoiesis of indeterminate potential (CHIP) is linked to increased heart failure (HF) risk, particularly non-DNMT3A subtypes. Comorbidities partially mediate this association, suggesting CHIP is a novel HF risk factor.
Area of Science:
- Cardiovascular Medicine
- Hematology
- Genetics
Background:
- Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition involving clonal expansion of hematopoietic cells with preleukemic mutations.
- CHIP has been associated with cardiometabolic diseases, including heart failure (HF), but less common CHIP driver variants and mediating factors remain understudied.
Purpose of the Study:
- To investigate the association between specific CHIP subtypes and incident HF.
- To determine the extent to which CHIP-associated comorbidities mediate the relationship between CHIP and HF.
Main Methods:
- A prospective, population-based cohort study using UK Biobank data from 2006-2020.
- Whole-exome sequencing (WES) was performed on participants without prevalent HF or hematologic malignancy.
- Cox regression models analyzed associations between CHIP/subtypes and incident HF, with mediation analyses for comorbidities (CAD, AF, T2D, CKD).
Main Results:
- Among 417,616 participants, CHIP was associated with increased HF risk (aHR, 1.27).
- Non-DNMT3A CHIP subtypes (TET2, ASXL1, JAK2, spliceosome) showed a stronger association with HF (aHR, 1.52).
- Comorbidities (CAD, AF, T2D, CKD) accounted for 28.2% of the non-DNMT3A CHIP-HF association.
Conclusions:
- CHIP, particularly non-DNMT3A subtypes, is significantly associated with incident heart failure.
- CHIP-associated comorbidities explain only a portion of the CHIP-HF link, indicating CHIP is an independent HF risk factor.
- These findings highlight CHIP as a potential therapeutic target for HF prevention.
Importance:
Clonal hematopoiesis of indeterminate potential (CHIP), the age-related clonal expansion of hematopoietic cells with acquired preleukemic variants, has been associated with cardiometabolic diseases, including heart failure (HF). However, prior studies have lacked power to examine less common CHIP driver variants and have not investigated potential mediators of the CHIP-HF association.
Objective:
To test whether specific CHIP subtypes are associated with incident HF and determine the extent to which CHIP-associated comorbidities mediate this association.
Design, Setting, And Participants:
This was a UK Biobank prospective population-based cohort study of community-dwelling adults in the UK, with enrollment from 2006 to 2010 and follow-up through 2020. Included were participants with whole-exome sequencing (WES) and without prevalent HF, hematologic malignancy, or other CHIP-associated comorbidities (coronary artery disease [CAD], atrial fibrillation [AF], type 2 diabetes [T2D], or chronic kidney disease [CKD]) at baseline. Study data were analyzed from April through October 2025.
Exposures:
Presence of CHIP and gene-specific CHIP subtypes (DNMT3A, non-DNMT3A, TET2, ASXL1, JAK2, DNA damage repair genes, and spliceosome genes). Mediation analyses examined CHIP-associated comorbidities (CAD, AF, T2D, and CKD).
Main Outcomes And Measures:
The primary outcome was incident HF. Cox regression tested associations of CHIP and CHIP subtypes with incident HF, adjusted for age, sex, race, and cardiovascular risk factors.
Results:
Among 417 616 participants (mean [SD] age, 56.1 [8.1] years; 234 868 female [56.2%]), 7183 (1.7%) developed incident HF over a median (IQR) of 11.1 (10.4-11.8) years of follow-up. CHIP was associated with HF risk (adjusted hazard ratio [aHR], 1.27; 95% CI, 1.15-1.40; P < .001), driven by non-DNMT3A subtypes (aHR, 1.52; 95% CI, 1.33-1.75; P < .001), including associations with TET2, ASXL1, JAK2, and spliceosome CHIP. DNMT3A CHIP was more modestly associated with HF (aHR, 1.15; 95% CI, 1.00-1.31; P = .04). In mediation analyses, development of CAD, AF, T2D, and/or CKD collectively accounted for 28.2% of the association (95% CI, 11.6%-45.4%; P = .001) between non-DNMT3A CHIP and HF.
Conclusions And Relevance:
Results of this cohort study suggest that CHIP, especially non-DNMT3A CHIP, was associated with incident HF. Other CHIP-associated comorbidities explained only a minority of the association between non-DNMT3A CHIP and HF. These findings suggest that CHIP is an HF risk factor and potential therapeutic target.
More Related Videos
08:14Lentiviral CRISPR/Cas9-Mediated Genome Editing for the Study of Hematopoietic Cells in Disease Models
Published on: October 3, 2019
09:32Clonal Analysis of Embryonic Hematopoietic Stem Cell Precursors Using Single Cell Index Sorting Combined with Endothelial Cell Niche Co-culture
Published on: May 8, 2018
Related Concept Videos
01:27Heart Failure I: Introduction
01:17Pathophysiology of Heart Failure
01:21Hematopoiesis
01:29Heart Failure II: Pathophysiology
01:19Multipotency of Hematopoietic Stem Cells
01:21Lineage Commitment