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oai:repisalud.isciii.es:20.500.12105/168102024-09-27T09:06:14Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Zekavat, Seyedeh M author Viana-Huete, Vanesa author Matesanz, Nuria author Jorshery, Saman Doroodgar author Zuriaga, María A author Uddin, Md Mesbah author Trinder, Mark author Paruchuri, Kaavya author Zorita, Virginia author Ferrer-Pérez, Alba author Amorós-Pérez, Marta author Kunderfranco, Paolo author Carriero, Roberta author Greco, Carolina M author Aroca-Crevillen, Alejandra author Hidalgo, Andres author Damrauer, Scott M author Ballantyne, Christie M author Niroula, Abhishek author Gibson, Christopher J author Pirruccello, James author Griffin, Gabriel author Ebert, Benjamin L author Libby, Peter author Fuster, Valentin author Zhao, Hongyu author Ghassemi, Marzyeh author Natarajan, Pradeep author Bick, Alexander G author Fuster, Jose J. author Klarin, Derek author 2023-01-16 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 TP53 and PPM1D. To model the effects of DDR-induced CHIP on atherosclerosis, we used a competitive bone marrow transplantation strategy, and generated atherosclerosis-prone Ldlr-/- 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. Nat Cardiovasc Res. 2023 Jan 16:2:144-158. http://hdl.handle.net/20.500.12105/16810 36949957 10.1038/s44161-022-00206-6 2731-0590 Nature cardiovascular research TP53-mediated clonal hematopoiesis confers increased risk for incident atherosclerotic disease.