JACC Journals › JACC › Archives › Vol. 81 No. 20

Clonal Hematopoiesis of Indeterminate Potential Predicts Adverse Outcomes in Patients With Atherosclerotic Cardiovascular DiseaseGET ACCESS

Original Investigation

Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA

Dr Gumuser and Mr Schuermans contributed equally and share first authorship.

Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusets, USA

Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA

Faculty of Medicine, KU Leuven, Leuven, Belgium

Dr Gumuser and Mr Schuermans contributed equally and share first authorship.

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So Mi Jemma Cho

Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusets, USA

Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA

Integrative Research Center for Cerebrovascular and Cardiovascular Diseases, Seoul, Korea

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Zachary A. Sporn

Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA

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Md Mesbah Uddin

Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusets, USA

Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA

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Kaavya Paruchuri

Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusets, USA

Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA

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Tetsushi Nakao

Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusets, USA

Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA

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Zhi Yu

Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusets, USA

Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA

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Sara Haidermota

Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusets, USA

Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA

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Whitney Hornsby

Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusets, USA

Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA

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Lachelle D. Weeks

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

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Abhishek Niroula

Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusets, USA

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

Department of Laboratory Medicine, Lund University, Lund, Sweden

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Siddhartha Jaiswal

Department of Pathology, Stanford University School of Medicine, Stanford, California, USA

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Peter Libby

Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA

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Benjamin L. Ebert

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

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Alexander G. Bick

Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA

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Pradeep Natarajan

Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA

Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusets, USA

Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA

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, and

Michael C. Honigberg

Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA

Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusets, USA

Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA

∗Address for correspondence: Dr Michael C. Honigberg, Massachusetts General Hospital, 185 Cambridge Street, CPZN 3.187, Boston, Massachusetts 02114, USA. E-mail:

E-mail Address: [email protected]

. Twitter: @mchonig.

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J Am Coll Cardiol. 2023 May, 81 (20) 1996–2009

Topic(s):

Genetics, Omics & Tissue Regeneration

Editorial Comment: Clonal Hematopoiesis in Patients With Atherosclerotic Cardiovascular Disease: One Step Closer to the Clinical Scenario^∗

Sections

About

Central Illustration

Abstract

Background

Clonal hematopoiesis of indeterminate potential (CHIP)—the age-related clonal expansion of blood stem cells with leukemia-associated mutations—is a novel cardiovascular risk factor. Whether CHIP remains prognostic in individuals with established atherosclerotic cardiovascular disease (ASCVD) is less clear.

Objectives

This study tested whether CHIP predicts adverse outcomes in individuals with established ASCVD.

Methods

Individuals aged 40 to 70 years from the UK Biobank with established ASCVD and available whole-exome sequences were analyzed. The primary outcome was a composite of ASCVD events and all-cause mortality. Associations of any CHIP (variant allele fraction ≥2%), large CHIP clones (variant allele fraction ≥10%), and the most commonly mutated driver genes (DNMT3A, TET2, ASXL1, JAK2, PPM1D/TP53 [DNA damage repair genes], and SF3B1/SRSF2/U2AF1 [spliceosome genes]) with incident outcomes were compared using unadjusted and multivariable-adjusted Cox regression.

Results

Of 13,129 individuals (median age: 63 years) included, 665 (5.1%) had CHIP. Over a median follow-up of 10.8 years, any CHIP and large CHIP at baseline were associated with adjusted HRs of 1.23 (95% CI: 1.10-1.38; P < 0.001) and 1.34 (95% CI: 1.17-1.53; P < 0.001), respectively, for the primary outcome. TET2 and spliceosome CHIP, especially large clones, were most strongly associated with adverse outcomes (large TET2 CHIP: HR: 1.89; 95% CI: 1.40-2.55; P <0.001; large spliceosome CHIP: HR: 3.02; 95% CI: 1.95-4.70; P < 0.001).

Conclusions

CHIP is independently associated with adverse outcomes in individuals with established ASCVD, with especially high risks observed in TET2 and SF3B1/SRSF2/U2AF1 CHIP.

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