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