Table 3.
Frequently mutated CHIP genes and associated mechanisms.
| Gene | Function of the gene |
Perturbed gene function | Putative pathologic mechanism |
Associated medical conditions |
|---|---|---|---|---|
| DNMT3A | Epigenetic regulation of gene expression (DNA de novo methylation) | Altered DNA methylation and epigenetic dysregulation | NLRP3 inflammasome activation (158) | CAD (45), Early-onset MI (24), incident CHD (24), chronic HF (51, 52), Ischemic (56)/hemorrhagic (55) stroke, aortic stenosis (59, 60), COPD (94, 95), PM (97), SS (98), RA (99), UC (100), chronic kidney disease (102), osteoporosis (103), chronic mycobacterial infection (105), HIV (107), MDS-HIV (106), solid tumor malignancies (35) |
| ↑ Th17/Treg ratio (60) | ||||
| ↑ TNF-α (95), IL-1ß (158), IL-6 (45, 158), IL-20 (103) | ||||
| ↑ CXCL1 (45), CXCL2 (45, 158), CXCL3 (45) | ||||
| ↑ CCL3, CCL4, resistin (158) | ||||
| ↑ CCR2, CALR, CYBA, LYZ, CXCL8, SELENOF, SLAMF6 (75) | ||||
| TET2 | Epigenetic regulation of gene expression (DNA demethylation) | Altered DNA methylation and epigenetic dysregulation | NLRP3 inflammasome activation (46, 65, 73) | CAD (24, 46, 47), early-onset MI (24), incident CHD (24), chronic HF (51–53), ischemic (55, 57)/total (55)/hemorrhagic (55) stroke, aortic stenosis (59, 60), pulmonary hypertension (63), diabetes (89), COPD (94), RA (99), chronic liver disease (101), chronic kidney disease (102), gout (104), HIV (107), solid tumor malignancies (35) |
| ↑ Nonclassical monocytes (60) | ||||
| ↑ IL-1ß (24, 57), IL-6 (24) | ||||
| ↑ CXCL1, CXCL2, CXCL3, Pf4 (24) | ||||
| ↑ IFN-γ levels (94) | ||||
| ↓ TGF-ß signaling (94) | ||||
| STING activation (159) | ||||
| ASXL1 | Epigenetic regulation of gene expression (Mono ubiquitination of H2A) | Aberrant chromatin remodeling | Akt/mTOR pathway activation (160) | Early-onset MI (24), incident CHD (24), HF (52, 53), stroke (55, 57), HIV (106–108), MDS-HIV (106), solid tumor malignancies (35) |
| ↓ T-cell infiltration at tumor sites (161) | ||||
| ↑ programmed death receptor-1 (PD-1) in CD8+ T cells (161) | ||||
| T cell dysregulation: aberrant intrathymic T-cell development, ↓ CD4/CD8 ratio, naïve-memory imbalance in peripheral T cells (161) | ||||
| JAK2 | Tyrosine kinase | Constitutive activation of JAK-STAT signaling pathway | AIM2 inflammasome activation (34) | CAD (48–50), early-onset MI (24), incident CHD (24), HF (53), ischemic stroke (58), venous thromboembolism (62), pulmonary hypertension (64), solid tumor malignancies (35) |
| ↑ neutrophil extracellular traps (62) | ||||
| ↑ burden of inflammatory macrophages within atherosclerotic lesions, necrotic core formation, and potential plaque instability (34) | ||||
| ↑ IL-1ß (34), IL-18 (80), ↑ IL-6 (80) | ||||
| TP53 | DNA damage repair, Cell cycle control | Disruption of cell cycle control and DNA damage response resulting in selective growth advantage to affected cells | ↑ H3K27 tri-methylation of genes regulating differentiation and HSC self-renewal (162) | HF (54), peripheral artery disease (61), solid tumor malignancies (35), t-AML (110) |
| ↑ reactive oxygen species (163) | ||||
| PPM1D | DNA damage repair, Cell cycle control | protein truncation in exon 6 resulting in impaired TP53 function, enhanced cell survival and resistance to DNA damage | ↑ reactive oxygen species (163) | HF (54), stroke (57), UC (100), SARS-CoV-2 (109), solid tumor malignancies (35), t-AML (110), t-MDS (110, 115) |
| ↑ IL-1ß, IL-18 (163) | ||||
| CHEK2 | DNA damage repair, cell cycle control | Enhanced cell survival and resistance to DNA damage | ↑ HSC self-renewal (164) | solid tumor malignancies (35), t-AML (38), secondary MDS (38) |
| SF3B1 | Splicing | Splicing factor dysfunction | ↑ IL-18 (80) | CAD (47), MDS (31, 36), solid tumor malignancies (35) |
| SRSF2 | Splicing | Splicing defects | ↓ EZH2 (165) | CAD (47), stroke (57), MDS (31, 36) |
| U2AF1 | Splicing | Splicing factor dysfunction | ↓ EZH2 (165) | CAD (47), MDS (31, 36), solid tumor malignancies (35) |
NLRP3, NOD-like receptor 3; TNF, Tumor necrosis factor; IL, Interleukin; IFN-γ, Interferon gamma; TGF-ß, Transforming growth factor ß; CHD, Coronary heart disease; MI, Myocardial infarction; HIV, Human immunodeficiency virus; (t-)MDS, (therapy-related) myelodysplastic syndromes; COPD, chronic obstructive pulmonary disease; PM, premature menopause; HF, heart failure; SS, systemic sclerosis; RA, rheumatoid arthritis; UC, ulcerative colitis; CAD, cardiovascular atherosclerotic disease; CHD, coronary heart disease; MPNs, myelodysplastic syndromes; (t-)AML, (therapy-related) acute myeloid leukemia.
The symbol ↑ means “increase”, whereas the symbol ↓ means “decrease”.