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Yu B, Roberts MB, Raffield LM, Zekavat SM, Nguyen NQH, Biggs ML, Brown MR, Griffin G, Desai P, Correa A, Morrison AC, Shah AM, Niroula A, Uddin MM, Honigberg MC, Ebert BL, Psaty BM, Whitsel EA, Manson JE, Kooperberg C, Bick AG, Ballantyne CM, Reiner AP, Natarajan P, Eaton CB, National Heart, Lung, and Blood Institute TOPMed Consortium
J. Am. Coll. Cardiol. 78 (1) 42-52 [2021-07-06; online 2021-07-03]
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). This study sought to evaluate whether CHIP is associated with incident HF. 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. 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. CHIP, particularly sequence variations in ASXL1, TET2, and JAK2, represents a new risk factor for HF.
PubMed 34210413
DOI 10.1016/j.jacc.2021.04.085
Crossref 10.1016/j.jacc.2021.04.085
mid: NIHMS1702439
pmc: PMC8313294
pii: S0735-1097(21)04975-5