Clonal hematopoiesis of indeterminate potential as a risk factor for atrial fibrillation: Evidence of a causal...

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.

This study aimed to assess the causal relationship between CHIP and AF and identify potential mediating pathways.

We conducted a bidirectional Mendelian randomization (MR) analysis using genome-wide association study data for CHIP from the UK Biobank (n = 368,526) and AF data from 2 large, independent cohorts (287,805 individuals from FinnGen and 1,030,836 from 6 additional AF studies). A 2-step MR mediation analysis was used to explore potential intermediate risk factors.

Inverse variance weighted MR analysis demonstrated a causal effect of CHIP on increased AF risk (meta-inverse variance weighted, odds ratio [OR] 1.057; P = .001), including both DNMT3a- and TET2-related CHIP (DNMT3a, OR 1.048, P = 4.56 × 10^-4; TET2, OR 1.038, P = .025). Causal associations between overall CHIP, including DNMT3a-CHIP, and AF were validated by a 2-sample MR study in 2 independent cohorts. Reverse MR showed no evidence of AF causing CHIP. The mediation analysis identified elevated systolic blood pressure as a key mediator in the DNMT3a-CHIP-AF pathway, accounting for 7.8% of the effect (P = .034).

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 systolic blood pressure was identified as a significant mediator linking DNMT3a-CHIP to AF.