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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Vydané v:	Nature communications Ročník 16; číslo 1; s. 4678 - 14
Hlavní autori:	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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 20.05.2025 Nature Publishing Group Nature Portfolio
Predmet:	13/1 13/100 13/31 38/91 45/22 45/23 45/41 631/208/176/1988 631/208/457 631/250/232 631/443/592/75 631/443/7 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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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-025-59333-w