Journal Article

TP53-mediated clonal hematopoiesis confers increased risk for incident atherosclerotic disease

Zuriaga, María A., Matesanz, Nuria, Greco, Carolina M., Ballantyne, Christie M., Trinder, Mark, Carriero, Roberta, Ebert, Benjamin L., Zorita, Virginia, Natarajan, Pradeep, Zekavat, Seyedeh M., Griffin, Gabriel, Bick, Alexander G., Damrauer, Scott M., Uddin, Md Mesbah, Fuster, José J., Ferrer-Pérez, Alba, Niroula, Abhishek, Gibson, Christopher J., Jorshery, Saman Doroodgar, Pirruccello, James, Aroca-Crevillen, Alejandra, Zhao, Hongyu, Ghassemi, Marzyeh, Fuster, Valentín, Hidalgo, Andrés, Viana-Huete, Vanesa, Paruchuri, Kaavya, Libby, Peter, Klarin, Derek, Amorós-Pérez, Marta, Kunderfranco, Paolo

2023

Overview

Somatic mutations in blood indicative of clonal hematopoiesis of indeterminate potential (CHIP) are associated with an increased risk of hematologic malignancy, coronary artery disease, and all-cause mortality. Here we analyze the relation between CHIP status and incident peripheral artery disease (PAD) and atherosclerosis, using whole-exome sequencing and clinical data from the UK Biobank and Mass General Brigham Biobank. CHIP associated with incident PAD and atherosclerotic disease across multiple beds, with increased risk among individuals with CHIP driven by mutation in DNA Damage Repair (DDR) genes such as and . To model the effects of DDR-induced CHIP on atherosclerosis, we used a competitive bone marrow transplantation strategy, and generated atherosclerosis-prone -/- chimeric mice carrying 20% p53-deficient hematopoietic cells. The chimeric mice were analyzed 13-weeks post-grafting and showed increased aortic plaque size and accumulation of macrophages within the plaque, driven by increased proliferation of p53-deficient plaque macrophages. In summary, our findings highlight the role of CHIP as a broad driver of atherosclerosis across the entire arterial system beyond the coronary arteries, and provide genetic and experimental support for a direct causal contribution of TP53-mutant CHIP to atherosclerosis.

• Publisher: Nature Publishing Group
• Subject: Aneurysms / Atherosclerosis / Biobanks / Cardiology and Cardiovascular Disease / Cell cycle / Clinical Medicine / Cloning / Electronic health records / Epigenetics / Genes / Kardiologi och kardiovaskulära sjukdomar / Klinisk medicin / Medical and Health Sciences / Medicin och hälsovetenskap / Meta-analysis / Mortality / Mutation / Sensitivity analysis / Vein & artery diseases