Work

Clonal hematopoiesis of indeterminate potential as a risk factor for atrial fibrillation: Evidence of a causal relationship by Mendelian randomization study

Year: 2025

Type: article

Abstract: Background Clonal hematopoiesis of indeterminate potential (CHIP) has emerged as an independent cardiovascular risk factor, with recent studies suggesting a link to atrial fibrillation (AF). However, the causal nature of this relationship, particularly the role of DNMT3a and TET2 mutations, remains unclear. Objective To assess the causal relationship between CHIP and AF and identify potential mediating pathways. Methods We conducted a bidirectional Mendelian randomization (MR) analysis using genome-wide association study (GWAS) data for CHIP from the UK Biobank (n = 368,526) and AF data from two large, independent cohorts (287,805 individuals from FinnGen and 1,030,836 from six additional AF studies). A two-step MR mediation analysis was used to explore potential intermediate risk factors. Results Inverse variance weighted (IVW) MR analysis demonstrated a causal effect of CHIP on increased AF risk (Meta-IVW: OR 1.057, P=0.001), including both DNMT3a- and TET2-related CHIP (DNMT3a: OR 1.048, P=4.56×10 -4 ; TET2: OR 1.038, P=0.025). Causal associations between overall CHIP, including DNMT3a-CHIP, and AF were validated by two-sample MR study in two independent cohorts. Reverse MR showed no evidence of AF causing CHIP. Mediation analysis identified elevated systolic blood pressure (SBP) as a key mediator in the DNMT3a-CHIP–AF pathway, accounting for 7.8% of the effect (P = 0.034). Conclusion Our findings provide genetic evidence that CHIP, particularly DNMT3a-related mutations, causally but modestly increases AF risk. There is no support for reverse causation. Elevated SBP was identified as a significant mediator linking DNMT3a-CHIP to AF.

Source: Heart Rhythm O2

DOI: 10.1016/j.hroo.2025.09.024