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

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 Libby, Benjamin L. Ebert, Christie M. Ballantyne () and Pradeep Natarajan ()
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Md Mesbah Uddin: Broad Institute of MIT and Harvard
Seyedmohammad Saadatagah: Baylor College of Medicine
Abhishek Niroula: Broad Institute of MIT and Harvard
Bing Yu: The University of Texas Health Science Center at Houston
Whitney E. Hornsby: Broad Institute of MIT and Harvard
Shriienidhie Ganesh: Broad Institute of MIT and Harvard
Kim Lannery: Broad Institute of MIT and Harvard
Art Schuermans: Broad Institute of MIT and Harvard
Michael C. Honigberg: Broad Institute of MIT and Harvard
Alexander G. Bick: Vanderbilt University Medical Center
Peter Libby: Harvard Medical School
Benjamin L. Ebert: Broad Institute of MIT and Harvard
Christie M. Ballantyne: Baylor College of Medicine
Pradeep Natarajan: Broad Institute of MIT and Harvard

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52302-9

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