# Clonal hematopoiesis associates with prevalent and incident cardiometabolic disease in a cardiac catheterization cohort

## TL;DR

This study finds that clonal hematopoiesis, especially large clones and non-DNMT3A mutations, is linked to heart disease and obesity in high-risk patients.

## Contribution

The study identifies specific CHIP clones and genes associated with cardiometabolic disease in a cardiac catheterization cohort.

## Key findings

- Large CHIP clones and non-DNMT3A CHIP variants are associated with prevalent heart failure and obesity.
- Non-DNMT3A CHIP increases the risk of heart failure hospitalization.
- CHIP is linked to incident cardiovascular events in high-risk individuals.

## Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is the age-related presence of expanded somatic clones secondary to leukemogenic driver mutations and is associated with cardiovascular (CV) disease and mortality. We sought to evaluate relationships between CHIP with cardiometabolic diseases and incident outcomes in high-risk individuals.

CHIP genotyping was performed in 8469 individuals referred for cardiac catheterization at Duke University (CATHGEN study) to identify variants present at a variant allele fraction (VAF) ≥2%. Associations were tested among any CHIP variant, large CHIP clones (VAF > 10%) and individual CHIP genes with prevalent cardiometabolic traits. Cox proportional hazard models tested CHIP associations with time-to-overall mortality and Fine-Gray analyses tested CHIP associations with incident cardiovascular outcomes.

We identified 463 CHIP variants in 427 individuals (5.0%) of which 268 (3.2%) harbored large CHIP clones. CHIP and large CHIP were associated with lower odds of obesity (OR 0.79 [95% CI 0.65–0.98], p = 0.03; OR 0.76 [95% CI 0.57–0.99], p = 0.04, respectively). CHIP was associated with prevalent heart failure (HF, OR 1.25 [95% CI 1.01–1.55], p = 0.04; especially for non-DNMT3A CHIP (OR 1.38 [95% CI 1.04–1.82], p = 0.02). CHIP was also associated with incident events: Non-DNMT3A CHIP was associated with increased risk of time-to-HF hospitalization (HR 1.29 [95% CI 1.02–1.63], p = 0.03).

In high-risk individuals referred for cardiac catheterization, large CHIP and non-DNTM3A CHIP were associated with obesity, prevalent HF, incident CV events. These findings strengthen the importance of CHIP as a biomarker for CV disease and highlight the contributing risk of large CHIP clones and non-DNMT3A CHIP variants.