Long-term longitudinal analysis of 4,187 participants reveals insights into determinants of clonal hematopoiesis
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.
Authors
- Kim Lannery (ORCID: https://orcid.org/0000-0001-5859-9093)
- Md Mesbah Uddin (ORCID: https://orcid.org/0000-0003-1846-0411)
- Alexander G. Bick (ORCID: https://orcid.org/0000-0001-5824-9595)
- Michael C. Honigberg (ORCID: https://orcid.org/0000-0001-8630-5021)
- Art Schuermans (ORCID: https://orcid.org/0000-0001-8146-9692)
- Abhishek Niroula (ORCID: https://orcid.org/0000-0002-5904-0635)
- Peter Libby (ORCID: https://orcid.org/0000-0002-1502-502X)
- Pradeep Natarajan (ORCID: https://orcid.org/0000-0001-8402-7435)
- Seyedmohammad Saadatagah
- Christie Mitchell Ballantyne (ORCID: https://orcid.org/0000-0002-6432-1730)
- Bing Yu (ORCID: https://orcid.org/0000-0003-4818-1077)
- Benjamin L. Ebert (ORCID: https://orcid.org/0000-0003-0197-5451)
- Whitney Hornsby (ORCID: https://orcid.org/0000-0002-0672-0338)
- Shriienidhie Ganesh (ORCID: https://orcid.org/0000-0002-4226-7526)
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- Baylor College of Medicine (US)
- Science for Life Laboratory (SE)
- Massachusetts General Hospital (US)
- Dana-Farber Cancer Institute (US)
- University of Gothenburg (SE)
- Vanderbilt University Medical Center (US)
- The University of Texas Health Science Center at Houston (US)
- KU Leuven (BE)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-09
- DOI
- https://doi.org/10.1038/s41467-024-52302-9
- Citations
- 31
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 14.09
Funders
- U.S. Department of Health and Human Services
- American Heart Association
- Alexander and Margaret Stewart Trust
- Massachusetts General Hospital
- Fondation Leducq
- Knut och Alice Wallenbergs Stiftelse
- National Institutes of Health
- National Heart, Lung, and Blood Institute