Non-DNMT3A CHIP Variants Linked to Higher Incident Heart Failure Risk in Older Adults

Clonal hematopoiesis of indeterminate potential (CHIP) subtypes, specifically non-DNMT3A genes, were associated with incident heart failure in older patients in a recent study published in JAMA Cardiology.1

CHIP affects 10% to 20% of individuals over the age of 70 years. Many subtypes or variants of CHIP are caused by a limited set of genes involved in epigenetic regulation, DNA damage repair, spliceosome machinery, or cell signaling. Previous research has noted increased risk in all-cause mortality, much of which is driven by cardiovascular disease. Yet, more recent research has linked CHIP as an independent risk factor of HF, specifically HF with preserved ejection fraction (HFpEF).2 However, due to overlapping comorbidities in which CHIP can occur and under-researched gene-specific associations, more research is required to quantify the risk association between CHIP and HF.1

The CHIP subtypes assessed in the study included any CHIP variant that was detectable by whole-exome sequencing (WES) and key gene-specific CHIP subtypes (DNMT3A CHIP, non-DNMT3A CHIP, and major non-DNMT3A subtypes: TET2, ASXL1, DNA damage repair genes [TP53 and PPM1D], spliceosome genes [SRSF2, SF3B1, U2AF1, PRPF8, and ZRSR2], and JAK2). The association between CHIP and HF was tested using the COX regression model and adjusted for demographic covariates.

A new study affirms prior research associating non-DNMT3A CHIP variants with higher heart failure risk. | Image credit: @CrazyJuke-stock.adobe.com.jpg

The large, prospective cohort study population consisted of 417,616 participants with a mean age of 56.1 years. Of them, 56.2% were female, 43.8% were male, and 3.3% (n=12,836) had CHIP. Race and ethnicity were self-identified: 2.2% of participants identified as Asian, 1.6% as Black, 0.6% as multiracial, 94.3% as White, and 0.9% as other. The most common CHIP subtype among participants was DNMT3A, which 8793 (63.5%) CHIP carriers had, followed by TET2 (n = 1987; 14.4%), ASXL1 (n = 1429; 10.3%), DNA damage repair genes (n = 599; 4.3%), spliceosome genes (n = 411; 3.0%), and JAK2 (n = 107; 0.8%).

Risk of HF With CHIP Variants

Overall, the incidence of heart failure was significantly higher in non-DNMT3A versus DNMT3A CHIP carriers (212 [4.1%] vs 222 [2.5%]; P < .001). Additionally, those with non-DNMT3A were also less likely to be female, were slightly older, and had higher high-sensitivity C-reactive protein levels when compared with DNMT3A CHIP carriers.

In the adjusted Cox regression models, significant associations with HF were observed for all subtypes except DNA repair genes (aHR, 1.39; 95% CI, 0.91-2.11; P = .13). In the analysis stratified by age (≥65 vs <65 years) or sex, there were no significant interactions between age; however, there was a significant interaction between sex and DNMT3A CHIP. There was a greater risk of HF associated with DNMT3A CHIP observed in females than in males (P = .04; aHR, 1.30; 95% CI, 1.08-1.56; P = .005 for incident HF in females).

The study was limited by its assessment of the DNMT3A R882 variant, which may underestimate its prevalence because the WES approach excluded variants with a variant allele frequency below 10%. Its findings are also limited by the predominantly European ancestry of the cohort and by evaluating CHIP only at baseline, which may miss newly emerging variants. Finally, the small number of R882 carriers restricts the power of subgroup analyses and limits mechanistic interpretation.

“Overall, these findings provide new insights into the association of various gene-specific CHIP subtypes with incident HF, with potential implications for targeted HF prevention and treatment,” the study authors concluded.

References

1. Flynn S, Schuermans A, Uddin MM, et al. Clonal hematopoiesis and incident heart failure. JAMA Cardiol. Published online November 09, 2025. doi:10.1001/jamacardio.2025.4603

2. Klein HE. TET2 chip an independent risk factor for HFPEF, study says. AJMC. January 26, 2024. Accessed November 24, 2025. https://www.ajmc.com/view/tet2-chip-an-independent-risk-factor-for-hfpef-study-says