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Long-term longitudinal analysis of 4,187 participants reveals insights into determinants of clonal hematopoiesis

Author

Listed:
  • Md Mesbah Uddin

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Seyedmohammad Saadatagah

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Abhishek Niroula

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    University of Gothenburg)

  • Bing Yu

    (The University of Texas Health Science Center at Houston)

  • Whitney E. Hornsby

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Shriienidhie Ganesh

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Kim Lannery

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Art Schuermans

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    KU Leuven)

  • Michael C. Honigberg

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

  • Alexander G. Bick

    (Vanderbilt University Medical Center)

  • Peter Libby

    (Harvard Medical School
    Brigham and Women’s Hospital)

  • Benjamin L. Ebert

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    Howard Hughes Medical Institute)

  • Christie M. Ballantyne

    (Baylor College of Medicine)

  • Pradeep Natarajan

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

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is linked to diverse aging-related diseases, including hematologic malignancy and atherosclerotic cardiovascular disease (ASCVD). While CHIP is common among older adults, the underlying factors driving its development are largely unknown. To address this, we performed whole-exome sequencing on 8,374 blood DNA samples collected from 4,187 Atherosclerosis Risk in Communities Study (ARIC) participants over a median follow-up of 21 years. During this period, 735 participants developed incident CHIP. Splicing factor genes (SF3B1, SRSF2, U2AF1, and ZRSR2) and TET2 CHIP grow significantly faster than DNMT3A non-R882 clones. We find that age at baseline and sex significantly influence the incidence of CHIP, while ASCVD and other traditional ASCVD risk factors do not exhibit such associations. Additionally, baseline synonymous passenger mutations are strongly associated with CHIP status and are predictive of new CHIP clone acquisition and clonal growth over extended follow-up, providing valuable insights into clonal dynamics of aging hematopoietic stem and progenitor cells. This study also reveals associations between germline genetic variants and incident CHIP. Our comprehensive longitudinal assessment yields insights into cell-intrinsic and -extrinsic factors contributing to the development and progression of CHIP clones in older adults.

Suggested Citation

  • Md Mesbah Uddin & Seyedmohammad Saadatagah & Abhishek Niroula & Bing Yu & Whitney E. Hornsby & Shriienidhie Ganesh & Kim Lannery & Art Schuermans & Michael C. Honigberg & Alexander G. Bick & Peter Lib, 2024. "Long-term longitudinal analysis of 4,187 participants reveals insights into determinants of clonal hematopoiesis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52302-9
    DOI: 10.1038/s41467-024-52302-9
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    References listed on IDEAS

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