SUMMARY Human aging is frequently accompanied by the acquisition of somatic mutations in the hematopoietic system that induce clonal hematopoiesis, leading to the development of a mutant clone of hematopoietic progenitors and leukocytes. This somatic-mutation-driven clonal hematopoiesis has been associated with an increased incidence of cardiovascular disease and type 2 diabetes, but whether this epidemiological association reflects a direct, causal contribution of mutant hematopoietic and immune cells to age-related metabolic abnormalities remains unexplored. Here, we show that inactivating mutations in the epigenetic regulator TET2, which lead to clonal hematopoiesis, aggravate age- and obesity-related insulin resistance in mice. This metabolic dysfunction is paralleled by increased expression of the pro-inflammatory cytokine IL-1β in white adipose tissue, and it is suppressed by pharmacological inhibition of NLRP3 inflammasome-mediated IL-1β production. These findings support a causal contribution of somatic TET2 mutations to insulin resistance and type 2 diabetes.

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Background: Somatic mutations in blood indicative of clonal hematopoiesis of indeterminate potential (CHIP), particularly in DNMT3A, TET2, and JAK2, are associated with an increased risk of hematologic malignancy, coronary artery disease, and all-cause mortality. However, whether CHIP is associated with increased risk of peripheral artery disease (PAD) remains unknown. In addition, chemotherapy frequently causes mutations in DNA Damage Repair (DDR) genes TP53 and PPM1D, and whether CHIP caused by somatic mutations in DDR genes results in increased risk of atherosclerosis is unclear. We sought to test whether CHIP, and CHIP caused by DDR genes, associates with incident peripheral artery disease (PAD) and atherosclerosis. Methods: We identified CHIP among 50,122 exome sequences in individuals from UK and Mass General Brigham Biobanks and tested CHIP status (N=2,851) with incident PAD and atherosclerosis across multiple arterial beds. To mimic the human scenario of clonal hematopoiesis and test whether the expansion of p53-deficient hematopoietic cells contributes to atherosclerosis, a competitive bone marrow transplantation (BMT) strategy was used to generate atherosclerosis-prone Ldlr-/- chimeric mice carrying 20% Trp53-/- hematopoietic cells (20% KO-BMT mice). We then evaluated aortic plaque burden and plaque macrophage accumulation 12 weeks after grafting. Results: CHIP associated with incident PAD (HR 1.7; P=2.2x10-5) and atherosclerosis in multiple beds (HR 1.3; P=9.7x10-5), with increased risk among individuals with DDR CHIP (HR 2.0; P=0.0084). Among atherosclerosis-prone Ldlr null mice, the p53 -/- 20% KO-BMT mice demonstrated increased aortic plaque size (p=0.013) and accumulation of p53-/- plaque macrophages (P<0.001), driven by an abundance of p53-deficient plaque macrophages. The expansion of p53-deficient cells did not affect the expression of the pro-inflammatory cytokines IL-6 and IL-1β in the atherosclerotic aortic wall. Conclusions: Our findings highlight the role of CHIP as a broad driver of atherosclerosis across the entire arterial system, with evidence of increased plaque among p53 -/- 20% KO-BMT mice via expansion of plaque macrophages. These observations provide new insight into the link between CHIP and cardiovascular disease, and lend human genetic support to the concept that post-cytotoxic chemotherapy patients may benefit from surveillance for atherosclerotic conditions in addition to therapy-related myeloid neoplasms.