Abstract
Background Clonal hematopoiesis of indeterminate potential (CHIP) was recently identified as a risk factor for incident heart failure (HF). Whether CHIP is associated selectively with risk of heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF) subtypes is unknown
Objectives To evaluate whether CHIP is associated with incident HF subtypes, HFrEF versus HFpEF.
Methods We obtained CHIP status from whole genome sequencing of blood DNA in participants without prevalent HF from a multi-ethnic sample of post-menopausal women without prevalent HF (N=5,214) from the Women’s Health Initiative (WHI). Cox proportional hazards models were performed, adjusting for demographic and clinical risk factors.
Results CHIP was significantly associated with a 42% (95%CI 6%, 91%) increased risk of HFpEF (P=0.02). In contrast, there was no evidence of association between CHIP and risk of incident HFrEF. When the three most common CHIP subtypes were assessed individually, the risk of HFpEF was more strongly associated with TET2 (HR=2.5; 95%CI 1.54, 4.06; P<0.001), than DNMT3A or ASXL1.
Conclusion CHIP, particularly mutations in TET2, represents a potential new risk factor for incident HFpEF.
Competing Interest Statement
MCH reports consulting fees from CRISPR Therapeutics, advisory board service for Miga Health, and research support from Genentech. PN has received grant support from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis; spousal employment and equity at Vertex; has received consulting income from Apple, AstraZeneca, Novartis, Genentech/Roche, Blackstone Edwards Lifesciences, Foresite Labs, and TenSixteen Bio; and has served on the scientific advisory board of and holds equity in TenSixteen Bio and geneXwell, all unrelated to this work. AGB is the founding scientific advisor to and a shareholder of TenSixteen Bio. PD has received research funding from Janssen Research. The remaining authors have nothing to disclose.
Funding Statement
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: Trans-Omics for Precision Medicine Whole Genome Sequencing Project: WGS for NHLBI TOPMed: Womens Health Initiative (WHI) (phs001237) was performed at the Broad Institute (HHSN268201500014C). 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). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. APR is supported by R01HL148565. MCH is supported by a grant from the National Heart, Lung, and Blood Institute (K08HL166687) and the American Heart Association (940166, 979465). PD reports funding from NCI (R01 CA248747, R01 CA260615) and DOD (W81XWH-22-1-0375). AGB has received support from a Burroughs Wellcome Foundation Career Award for Medical Scientists and the NIH Director Early Independence Award (DP5-OD029586). PN is supported by grants from the National Heart, Lung, and Blood Institute (R01HL142711, R01HL148050, R01HL148565) and Fondation Leducq (TNE-18CVD04).
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
The Institutional Review Board at the Fred Hutchinson Cancer Center approved the studies and participants provided written informed consent.
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Data Availability
All data produced in the present study are available upon reasonable request to the authors.