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<p>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 (<i>N</i> = 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 <i>p</i>-value &lt; 0.05). Taken together, our study reports the epigenetic changes impacted by CHIP and their associations with age-related disease outcomes.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年5月20日

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  • Sara Kirmani,
  • Tianxiao Huan,
  • Joseph C. Van Amburg,
  • Roby Joehanes,
  • Md Mesbah Uddin,
  • Ngoc Quynh H. Nguyen,
  • Bing Yu,
  • Jennifer A. Brody,
  • Myriam Fornage,
  • Jan Bressler,
  • Nona Sotoodehnia,
  • David A. Ong,
  • Fabio Puddu,
  • James S. Floyd,
  • Christie M. Ballantyne,
  • Bruce M. Psaty,
  • Laura M. Raffield,
  • Pradeep Natarajan,
  • Karen N. Conneely,
  • Joshua S. Weinstock,
  • April P. Carson,
  • Leslie A. Lange,
  • Kendra Ferrier,
  • Nancy L. Heard-Costa,
  • Joanne Murabito,
  • Alexander G. Bick,
  • Daniel Levy

摘要

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.