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

Zekavat SM, Viana-Huete V, Matesanz N, Jorshery SD, Zuriaga MA, Uddin MM, Trinder M, Paruchuri K, Zorita V, Ferrer-Pérez A, Amorós-Pérez M, Kunderfranco P, Carriero R, Greco CM, Aroca-Crevillen A, Hidalgo A, Damrauer SM, Ballantyne CM, Niroula A, Gibson CJ, Pirruccello J, Griffin G, Ebert BL, Libby P, Fuster V, Zhao H, Ghassemi M, Natarajan P, Bick AG, Fuster JJ, Klarin D

Nat Cardiovasc Res 2 (-) 144-158 [2023-01-16; online 2023-03-24]

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.

Abhishek Niroula

DDLS Fellow

PubMed 36949957

DOI 10.1038/s44161-022-00206-6

Crossref 10.1038/s44161-022-00206-6

mid: NIHMS1875484
pmc: PMC10026701

Publications 9.5.0