Faculty, Staff and Student Publications
Publication Date
5-20-2025
Journal
Nature Communications
Abstract
With age, hematopoietic stem cells can acquire somatic mutations in leukemogenic genes that confer a proliferative advantage in a phenomenon termed CHIP. How these mutations result in increased risk for numerous age-related diseases remains poorly understood. We conduct a multiracial meta-analysis of EWAS of CHIP in the Framingham Heart Study, Jackson Heart Study, Cardiovascular Health Study, and Atherosclerosis Risk in Communities cohorts (N = 8196) to elucidate the molecular mechanisms underlying CHIP and illuminate how these changes influence cardiovascular disease risk. We functionally validate the EWAS findings using human hematopoietic stem cell models of CHIP. We then use expression quantitative trait methylation analysis to identify transcriptomic changes associated with CHIP-associated CpGs. Causal inference analyses reveal 261 CHIP-associated CpGs associated with cardiovascular traits and all-cause mortality (FDR adjusted p-value < 0.05). Taken together, our study reports the epigenetic changes impacted by CHIP and their associations with age-related disease outcomes.
Keywords
Humans, DNA Methylation, Epigenome, CpG Islands, Epigenesis, Genetic, Gene Expression Regulation, Male, Cardiovascular Diseases, Female, Hematopoietic Stem Cells, Genome-Wide Association Study, Middle Aged, Aged, Atherosclerosis
DOI
10.1038/s41467-025-59333-w
PMID
40393957
PMCID
PMC12092741
PubMedCentral® Posted Date
5-20-2025
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes