Supplemental Association of Clonal Hematopoiesis With Incident Heart Failure.

Abstract

BACKGROUND:

Age-related clonal hematopoiesis of indeterminate potential (CHIP), defined as clonally expanded leukemogenic sequence variations (particularly in DNMT3A, TET2, ASXL1, and JAK2) in asymptomatic individuals, is associated with cardiovascular events, including recurrent heart failure (HF).

OBJECTIVES:

This study sought to evaluate whether CHIP is associated with incident HF.

METHODS:

CHIP status was obtained from whole exome or genome sequencing of blood DNA in participants without prevalent HF or hematological malignancy from 5 cohorts. Cox proportional hazards models were performed within each cohort, adjusting for demographic and clinical risk factors, followed by fixed-effect meta-analyses. Large CHIP clones (defined as variant allele frequency >10%), HF with or without baseline coronary heart disease, and left ventricular ejection fraction were evaluated in secondary analyses.

RESULTS:

Of 56,597 individuals (59% women, mean age 58 years at baseline), 3,406 (6%) had CHIP, and 4,694 developed HF (8.3%) over up to 20 years of follow-up. CHIP was prospectively associated with a 25% increased risk of HF in meta-analysis (hazard ratio: 1.25; 95% confidence interval: 1.13-1.38) with consistent associations across cohorts. ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP was associated with a greater risk of HF (hazard ratio: 1.29; 95% confidence interval: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. ASXL1 sequence variations were associated with reduced left ventricular ejection fraction.

CONCLUSIONS:

CHIP, particularly sequence variations in ASXL1, TET2, and JAK2, represents a new risk factor for HF.

• Authors: Bing Yu, Mary B Roberts, Laura M Raffield, Seyedeh Maryam Zekavat, Ngoc Quynh H Nguyen, Mary L Biggs, Michael R Brown, Gabriel Griffin, Pinkal Desai, Adolfo Correa, Alanna C Morrison, Amil M Shah, Abhishek Niroula, Md Mesbah Uddin, Michael C Honigberg, Benjamin L Ebert, Bruce M Psaty, Eric A Whitsel, JoAnn E Manson, Charles Kooperberg, Alexander G Bick, Christie M Ballantyne, Alex P Reiner, Pradeep Natarajan, Charles B Eaton, National Heart, Lung, and Blood Institute TOPMed Consortium
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 78 Issue 1 Pg. 42-52 (07 06 2021) ISSN: 1558-3597 [Electronic] United States
• PMID: 34210413 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Chemical References

• ASXL1 protein, human
• DNA-Binding Proteins
• Proto-Oncogene Proteins
• Repressor Proteins
• Dioxygenases
• TET2 protein, human
• JAK2 protein, human
• Janus Kinase 2

Topics

• Aged
• Clonal Hematopoiesis (genetics)
• Correlation of Data
• DNA-Binding Proteins (genetics)
• Demography
• Dioxygenases
• Female
• Heart Failure (diagnosis, epidemiology, physiopathology)
• Humans
• Janus Kinase 2 (genetics)
• Male
• Middle Aged
• Mutation
• Proportional Hazards Models
• Proto-Oncogene Proteins (genetics)
• Repressor Proteins (genetics)
• Risk Factors
• Stroke Volume
• Ventricular Dysfunction, Left (diagnosis, genetics)
• Exome Sequencing (methods)