Epigenome-wide DNA methylation association study of CHIP provides insight into perturbed gene regulation

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 o...

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Veröffentlicht in:Nature communications Jg. 16; H. 1; S. 4678 - 14
Hauptverfasser: Kirmani, Sara, Huan, Tianxiao, Van Amburg, Joseph C., Joehanes, Roby, Uddin, Md Mesbah, Nguyen, Ngoc Quynh H., Yu, Bing, Brody, Jennifer A., Fornage, Myriam, Bressler, Jan, Sotoodehnia, Nona, Ong, David A., Puddu, Fabio, Floyd, James S., Ballantyne, Christie M., Psaty, Bruce M., Raffield, Laura M., Natarajan, Pradeep, Conneely, Karen N., Weinstock, Joshua S., Carson, April P., Lange, Leslie A., Ferrier, Kendra, Heard-Costa, Nancy L., Murabito, Joanne, Bick, Alexander G., Levy, Daniel
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 20.05.2025
Nature Publishing Group
Nature Portfolio
Schlagworte:
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Age
Age related diseases
Aged
Arteriosclerosis
Atherosclerosis
Atherosclerosis - genetics
Blood cells
Cardiovascular diseases
Cardiovascular Diseases - genetics
Cardiovascular Diseases - mortality
Cell culture
CpG Islands - genetics
DNA methylation
DNA Methylation - genetics
Epigenesis, Genetic
Epigenetics
Epigenome - genetics
Female
Gene Expression Regulation
Gene regulation
Genome-Wide Association Study
Health risks
Hematopoietic stem cells
Hematopoietic Stem Cells - metabolism
Humanities and Social Sciences
Humans
Male
Middle Aged
Molecular modelling
multidisciplinary
Mutation
Risk
Science
Science (multidisciplinary)
Stem cells
Transcriptomics
ISSN:2041-1723, 2041-1723
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Zusammenfassung: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. In CHIP, somatic mutations in a hematopoietic stem cell lead to a clonal subpopulation of blood cells. Here, the authors perform a CHIP meta-EWAS to establish its epigenetic features and age-related outcomes.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-025-59333-w