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. 2021 Jul 6;78(1):42-52.
doi: 10.1016/j.jacc.2021.04.085.

Supplemental Association of Clonal Hematopoiesis With Incident Heart Failure

Bing Yu  1 , Mary B Roberts  2 , Laura M Raffield  3 , Seyedeh Maryam Zekavat  4 , Ngoc Quynh H Nguyen  1 , Mary L Biggs  5 , Michael R Brown  1 , Gabriel Griffin  6 , Pinkal Desai  7 , Adolfo Correa  8 , Alanna C Morrison  1 , Amil M Shah  9 , Abhishek Niroula  10 , Md Mesbah Uddin  11 , Michael C Honigberg  12 , Benjamin L Ebert  13 , Bruce M Psaty  14 , Eric A Whitsel  15 , JoAnn E Manson  16 , Charles Kooperberg  17 , Alexander G Bick  18 , Christie M Ballantyne  19 , Alex P Reiner  17 , Pradeep Natarajan  20 , Charles B Eaton  21 ; National Heart, Lung, and Blood Institute TOPMed Consortium
Affiliations

Supplemental Association of Clonal Hematopoiesis With Incident Heart Failure

Bing Yu et al. J Am Coll Cardiol. .

Erratum in

  • Correction.
    [No authors listed] [No authors listed] J Am Coll Cardiol. 2021 Aug 17;78(7):762. doi: 10.1016/j.jacc.2021.06.032. J Am Coll Cardiol. 2021. PMID: 34384560 No abstract available.

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.

Keywords: clonal hematopoiesis of indeterminate potential; heart failure; risk factor.

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Conflict of interest statement

Funding Support and Author Disclosures Whole genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI). WGS for “NHLBI TOPMed: The Jackson Heart Study” (phs000964) was performed at the University of Washington Northwest Genomics Center (HHSN268201100037C). WGS for “NHLBI TOPMed: Women's Health Initiative (WHI)” (phs001237) was performed at the Broad Institute (HHSN268201500014C). WGS for “NHLBI TOPMed: Trans-Omics for Precision Medicine (TOPMed) Whole Genome Sequencing Project: Cardiovascular Health Study” (phs001368) was performed at Baylor (HHSN268201600033I, 3U54HG003273-12S2/HHSN268201500015C). Centralized read mapping and genotype calling along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1; contract HHSN268201800001I). The Atherosclerosis Risk In Communities study has been funded in whole or in part with federal funds from the NHLBI, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I). Funding support for “Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium” was provided by the National Institutes of Health through the American Recovery and Reinvestment Act of 2009 (5RC2HL102419). Whole exome sequencing was carried out at the Baylor College of Medicine Human Genome Sequencing Center (U54 HG003273 and R01HL086694). The CHS (Cardiovascular Health Study) was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and 75N92021D00006, and by grants U01HL080295 and U01HL130114 from the NHLBI, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by R01AG023629 from the National Institute on Aging. The JHS (Jackson Heart Study) is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I), and the University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I, and HHSN268201800012I) contracts from the NHLBI and the National Institute on Minority Health and Health Disparities. The WHI program is funded by the NHLBI, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. Dr Yu is supported in part by R01HL141824 and R01HL148050. Dr Raffield was funded by T32 HL129982 and KL2TR00249. Dr Zekavat is supported by the National Institutes of Health’s NHLBI under award number 1F30HL149180-01 and the National Institutes of Health’s Medical Scientist Training Program at the Yale School of Medicine. Dr Shah is supported in part by grants from the NHLBI (R01HL135008, R01HL143224, R01HL150342, R01HL14818, and K24HL152008); has received research support from Novartis and Philips Ultrasound through Brigham and Women's Hospital; and has received consulting fees from Philips Ultrasound and Edwards Lifesciences. Dr Honigberg is supported by a grant from the NHLBI (T32HL094301-07). Dr Ebert has received research funding from Celgene, Deerfield, and Novartis; has received consulting fees from GRAIL; and has served on the scientific advisory boards and holds equity in Skyhawk Therapeutics, Exo Therapeutics, and Neomorph Therapeutics. Dr Reiner is supported by R01HL148565. Dr Natarajan is supported by grants from the NHLBI (R01HL142711, R01HL148050, R01HL148565) and Fondation Leducq (TNE-18CVD04); has received grants from Amgen, Apple, Boston Scientific, and Novartis; has received consulting income from Apple, Blackstone Life Sciences, Novartis, and Genentech; and has spousal employment at Vertex, all unrelated to the present work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

Figure 1.
Figure 1.. Clonal hematopoiesis in individual genes and incident heart failure.
Individual genes analyzed include a) ASXL1, b) DNMT3A, c) JAK2 and d) TET2. Event represents the number of incident heart failure cases. For each gene, multivariable adjusted hazard ratios and 95% CIs were calculated separately in each study adjusting for age, sex, education, diabetes mellitus, smoking status, stroke, coronary heart disease, systolic blood pressure, hypertension medication use, body mass index, and race (if more than one) and combined using a fixed-effect meta-analysis. Abbreviations as in Central Illustration.
Figure 2.
Figure 2.. Associations for somatic mutation and heart failure subgroups.
a) clonal hematopoiesis of indeterminate potential with variant allele frequency > 10% and incident heart failure, b) clonal hematopoiesis of indeterminate potential and incident heart failure without prior coronary heart disease, and c) clonal hematopoiesis of indeterminate potential and incident heart failure with prior coronary heart disease. Event represents the number of incident heart failure cases. For each model, multivariable adjusted hazard ratios and 95% CIs were calculated separately in each study adjusting for age, sex, education, diabetes mellitus, smoking status, stroke, coronary heart disease, systolic blood pressure, hypertension medication use, body mass index, and race (if more than one) and combined using a fixed-effect meta-analysis. Coronary heart disease status was not adjusted in the associations of heart failure with or without prior coronary heart disease. Abbreviations as in Central Illustration.
Figure 3.
Figure 3.. Clonal hematopoiesis and left ventricular ejection fraction in UK Biobank.
Association of clonal hematopoiesis of indeterminate potential status with left ventricular ejection fraction was performed using a linear regression with the adjustments of age, sex, smoking status, prevalent coronary heart disease, diabetes, systolic blood pressure, and self-reported race in the UK Biobank participants. Unadjusted first quartile, median, and third quartile of left ventricular ejection fraction were presented in the boxplots, and outliers were presented as dots. LVEF = left ventricular ejection fraction; other abbreviations as in Central Illustration.
Central Illustration.
Central Illustration.. Clonal hematopoiesis of indeterminate potential mutation and incident heart failure.
Clonal hematopoiesis of indeterminate potential, determined by whole exome or genome sequencing, was significantly associated with an increased risk of heart failure in five prospective studies including 56,597 African, European and Hispanic populations with up to 20 years follow-up. Multivariable adjusted hazard ratios and 95% CIs were calculated separately in each study adjusting for age, sex, education, diabetes mellitus, smoking status, stroke, coronary heart disease, systolic blood pressure, hypertension medication use, body mass index, and race (if more than one) and combined using a fixed-effect meta-analysis. CHIP = clonal hematopoiesis of indeterminate potential; ARIC = Atherosclerosis Risk in Communities Study; CHS = Cardiovascular Health Study; JHS = Jackson Heart Study; UKBB = United Kingdom Biobank; WHI = Women’s Health Initiative.
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