Table 1.
Significant Studies Investigating CHIP-Associated CVD
| Study | Hematopoietic Cell Types | Key Findings |
|---|---|---|
| Jaiswal et al. (2014) | N/A | Increased risks of hematologic cancer, all-cause mortality, coronary heart disease, and ischemic stroke were observed in individuals with CHIP. Mutations in DNMT3A, TET2, and ASXL1 constituted most of the CHIP variants in this study. |
| Montagner et al. (2016) | Mast cells | TET2 regulated mast cell differentiation. Upon IgE and antigen stimulation, Tet2-deficient mast cells produced reduced levels of the mast cell cytokines IL-6, TNF-α, and IL-13. |
| Cull et al. (2017) | Macrophages | TET2 prevented inflammation and was highly expressed during macrophage differentiation. Tet2 loss led to increased Il-1β, Il-6, and Arginase 1 during later stages of LPS stimulation of BM-derived macrophages. |
| Fuster et al. (2017) | Macrophages | In Ldlr-deficient mice transplanted with Tet2-deficient BM cells, pro-inflammatory Tet2-deficient macrophages increased the secretion of IL-1β via the NLRP3 inflammasome. TET2 regulated expression of the NLRP3. inflammasome. Inhibition of the NLRP3 inflammasome impaired the growth of atherosclerotic plaques. |
| Jaiswal et al. (2017) | N/A | Increased risks of coronary heart disease, coronary-artery calcification, and early-onset myocardial infarction were observed in individuals with CHIP. Ldlr-deficient mice transplanted with BM from Tet2-deficient mice exhibited accelerated atherosclerosis. Increased RNA and protein expression of IL-1β, IL-6, CXCL1, CXCL2, CXCL3, and PF-4 was measured in these transplanted mice. Increased expression of IL-8 was detected in the plasma of individuals with CHIP. |
| Leoni et al. (2017) | Mast cells | DNMT3A attenuated mast cell responses to acute and chronic stimuli. Loss of Dnmt3a was associated with increased sensitivity to stimuli, increased cytokine release, and enhanced degranulation capacity. |
| Abegunde et al. (2018) | HSPCs | Chronic TNF-α exposure promoted a clonogenic advantage for murine Tet2-deficient and human TET2-mutant HSPCs in vitro. The expansion of these HSPCs coincided with resistance to apoptosis and myeloid skewing. This study suggests an important role for HSPCs carrying CHIP-associated mutations, in addition to mature hematopoietic lineages. |
| Buscarlet et al. (2018) | N/A | Patients with CHIP-associated mutations in TET2 or DNMT3A exhibited different hematopoietic lineages. TET2 mutations correlated with greater myeloid populations and no multipotent lineages, whereas DNMT3A mutations coincided with multipotent lineages. The kinetics of clonal expansion differed with distinct CHIP-associated mutations. |
| Cai et al. (2018) | HSPCs and myeloid cells | Increased Tet2-deficient mature myeloid cells and HSPCs were detected in response to inflammatory stress, leading to enhanced production of inflammatory cytokines, such as IL-6. The long non-coding RNA Morrbid was increased in response to IL-6. Inhibition of SHP2 or STAT3 or loss of Morrbid inhibited CH of Tet2-deficient HSPCs. |
| Sano et al. (2018a) | Macrophages | In response to angiotensin II, mice lacking either Tet2 or Dnmt3a developed cardiac hypertrophy, cardiac and renal fibrosis, and reduced cardiac function. The kinetics of clonal expansion differed in Tet2- and Dnmt3a-deficient mice. Increased expression of Il-1β, Il-6, and Ccl5 was detected in an LPS-stimulated Tet2-deficient macrophage cell line, whereas elevation of Cxcl1, Cxcl2, Il-6, and Ccl5 was observed in an LPS-stimulated Dnmt3a-deficient macrophage cell line. |
| Sano et al. (2018b) | Macrophages | Tet2-deficient hematopoietic or myeloid cells exacerbated cardiac remodeling and function and correlated with increased IL-1β expression in transaortic constriction and chronic ischemia models of heart failure. Inhibition of the NLRP3 inflammasome improved cardiac measurements and alleviated heart failure development. |
| Wolach et al. (2018) | Neutrophils | CH for JAK2V617F, the most common driver of myeloproliferative neoplasm, correlated with an increased occurrence of thrombosis. Mice expressing JAK2V617F exhibited increased NET formation and thrombosis, which were alleviated by the JAK2 inhibitor ruxolitinib. |
| Cook et al. (2019) | N/A | Elevated expression of IL-6, MCP1/CCL2, and TNF-α was detected in individuals with CHIP. |
| Dorsheimer et al. (2019) | N/A | Patients with CHIP often had a history of hypertension. Mutations in TET2 or DNMT3A were associated with worse heart failure outcomes. |
| Mudersbach et al. (2019) | N/A | In response to TNF-α stimulation of endothelial cells, increased methylation was detected at sites in the ACE promoter in a DNMT3A- and DNMT3B-dependent manner. |
| Sano et al. (2019) | Myeloid cells | Mice with myeloid expression of the JAK2V617F mutation demonstrated increased cardiac inflammation and dysfunction after permanent left anterior descending artery ligation and transverse aortic constriction. |
| Bick et al. (2020) | N/A | Individuals with large CHIP clones (VAF > 10%) that also carry an IL-6 receptor p.Asp358Ala mutation exhibited fewer CVD events. |
| Mas-Peiro et al. (2020) | T cells and myeloid cells | Patients with aortic valve stenosis undergoing transcatheter aortic valve implantation and carrying TET2 or DNMT3A mutations experienced worse outcomes. Patients with TET2 mutations showed increased pro-inflammatory non-classical monocytes, whereas patients with DNMT3A mutations exhibited pro-inflammatory T cell polarization. |
| Veninga et al. (2020) | Platelets | Mutations in different CHIP-associated genes were linked to differences in platelet number and risk of thrombosis and bleeding. |
| Wang et al. (2020) | Myeloid cells | Transplantation of Tet2-deficient BM cells into non-irradiated recipient mice resulted in cardiac dysfunction, hypertrophy, and fibrosis. Macrophages isolated from the heart exhibited upregulation of cytokines, cytokine receptors, and interferon-related genes and downregulation of genes involved in regulation of cell differentiation and neurogenesis. |
ACE, angiotensin-converting enzyme; ASXL1, Associated sex combs-like 1; BM, bone marrow; CHIP, clonal hematopoiesis of indeterminate potential; CCL2, C-C motif chemokine ligand 2; Ccl5, C-C motif chemokine ligand 5; CXCL1, CXC motif chemokine ligand 1; CXCL2, CXC motif chemokine ligand 2; CXCL3, CXC motif chemokine ligand 3; DNMT3A, DNA methyltransferase 3a; DNMT3B, DNA methyltransferase 3b; HSPCs, hematopoietic stem and progenitor cells; IgE, immunoglobulin E; IL-1β, interleukin-1β; IL-6, interleukin-6; IL-8, interleukin-8; IL-13, interleukin-13; JAK2, Janus-associated kinase 2; Ldlr, low-density lipoprotein receptor; LPS, lipopolysaccharide; MCP1, monocyte chemoattractant protein 1; NET, neutrophil extracellular trap; NLRP3, NOD-, LRR-, and pyrin domain-containing protein 3; PF-4, platelet factor 4; SHP2, Src homology phosphatase 2; STAT3, signal transducer and activator of transcription 3; TET2, Tet methylcytosine dioxygenase 2; TNF-α, tumor necrosis factor-α; VAF, variant allele frequency; N/A, not applicable.