Faculty, Staff and Student Publications
Publication Date
9-9-2024
Journal
Nature Communications
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.
Keywords
Humans, Clonal Hematopoiesis, Male, Female, Aged, Longitudinal Studies, Middle Aged, Dioxygenases, DNA Methyltransferase 3A, RNA Splicing Factors, Atherosclerosis, Risk Factors, Exome Sequencing, DNA-Binding Proteins, Proto-Oncogene Proteins, DNA (Cytosine-5-)-Methyltransferases, Hematopoietic Stem Cells, Aging, Incidence, Mutation, Genetic variation, Risk factors, Personalized medicine
DOI
10.1038/s41467-024-52302-9
PMID
39251642
PMCID
PMC11385577
PubMedCentral® Posted Date
9-9-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes