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Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease

Author

Listed:
  • M d Mesbah Uddin

    (Broad Institute of Harvard and MIT
    Massachusetts General Hospital)

  • Ngoc Quynh H. Nguyen

    (The University of Texas Health Science Center at Houston)

  • Bing Yu

    (The University of Texas Health Science Center at Houston)

  • Jennifer A. Brody

    (University of Washington)

  • Akhil Pampana

    (Broad Institute of Harvard and MIT)

  • Tetsushi Nakao

    (Broad Institute of Harvard and MIT
    Massachusetts General Hospital
    Dana-Farber Cancer Institute
    Brigham and Women’s Hospital)

  • Myriam Fornage

    (University of Texas Health Science Center at Houston
    University of Texas Health Science Center at Houston)

  • Jan Bressler

    (The University of Texas Health Science Center at Houston
    University of Texas Health Science Center at Houston)

  • Nona Sotoodehnia

    (University of Washington)

  • Joshua S. Weinstock

    (University of Michigan School of Public Health)

  • Michael C. Honigberg

    (Broad Institute of Harvard and MIT
    Massachusetts General Hospital)

  • Daniel Nachun

    (Stanford University School of Medicine)

  • Romit Bhattacharya

    (Broad Institute of Harvard and MIT
    Massachusetts General Hospital
    Harvard Medical School)

  • Gabriel K. Griffin

    (Dana-Farber Cancer Institute
    Brigham and Women’s Hospital
    Broad Institute of MIT and Harvard)

  • Varuna Chander

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Richard A. Gibbs

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Jerome I. Rotter

    (The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center)

  • Chunyu Liu

    (School of Public Health, Boston University
    Boston University and NHLBI/NIH)

  • Andrea A. Baccarelli

    (Columbia University)

  • Daniel I. Chasman

    (Harvard Medical School
    Brigham and Women’s Hospital)

  • Eric A. Whitsel

    (University of North Carolina
    University of North Carolina)

  • Douglas P. Kiel

    (Harvard Medical School
    Hebrew SeniorLife
    Beth Israel Deaconess Medical Center
    Broad Institute of Harvard and MIT)

  • Joanne M. Murabito

    (Boston University and NHLBI/NIH
    Boston University School of Medicine and Boston Medical Center)

  • Eric Boerwinkle

    (The University of Texas Health Science Center at Houston
    University of Texas Health Science Center at Houston
    Baylor College of Medicine)

  • Benjamin L. Ebert

    (Dana-Farber Cancer Institute
    Howard Hughes Medical Institute)

  • Siddhartha Jaiswal

    (Stanford University School of Medicine)

  • James S. Floyd

    (University of Washington
    University of Washington)

  • Alexander G. Bick

    (Vanderbilt University Medical Center)

  • Christie M. Ballantyne

    (Baylor College of Medicine)

  • Bruce M. Psaty

    (University of Washington
    University of Washington
    University of Washington)

  • Pradeep Natarajan

    (Broad Institute of Harvard and MIT
    Massachusetts General Hospital
    Harvard Medical School)

  • Karen N. Conneely

    (Emory University School of Medicine)

Abstract

Age-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association study for CHIP in 582 Cardiovascular Health Study (CHS) participants, with replication in 2655 Atherosclerosis Risk in Communities (ARIC) Study participants. We show that DNMT3A and TET2 CHIP have distinct and directionally opposing genome-wide DNAm association patterns consistent with their regulatory roles, albeit both promoting self-renewal of HSCs. Mendelian randomization analyses indicate that a subset of DNAm alterations associated with these two leading CHIP genes may promote the risk for CAD.

Suggested Citation

  • M d Mesbah Uddin & Ngoc Quynh H. Nguyen & Bing Yu & Jennifer A. Brody & Akhil Pampana & Tetsushi Nakao & Myriam Fornage & Jan Bressler & Nona Sotoodehnia & Joshua S. Weinstock & Michael C. Honigberg &, 2022. "Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33093-3
    DOI: 10.1038/s41467-022-33093-3
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    References listed on IDEAS

    as
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