ABSTRACT
Age is the most important risk factor for cardiovascular disease and appears to be
more than a marker of cumulative exposure to other risk factors such as dyslipidemia
and hypertension. With aging, genetic mutations occur that are not present in our
germline DNA, observed as somatic mosaicism. Hematopoietic stem cells have an increased
chance of developing mosaicism because they are highly proliferative, and mutations
with survival benefits can establish clonal populations. Age-related clonal hematopoiesis
resulting from somatic mutations was first described ∼25 years ago. The subset of
clonal hematopoiesis in which a driver mutation with variant allele frequency of at
least 2% occurs in a gene implicated in hematologic malignancies but in the absence
of known hematologic malignancy or other clonal disorder is termed clonal hematopoiesis
of indeterminate potential (CHIP). Large-scale exome-sequencing projects have recently
enabled the study of CHIP frequency, gene-specific analyses, and longitudinal clinical
consequences of CHIP, including an observed increased risk for cardiovascular disease.
Animal models provide insight into the mechanisms by which CHIP increases cardiovascular
disease risk, and combined animal, clinical, and epidemiological data suggest therapeutic
implications for CHIP in cardiovascular disease prevention.
Abbreviations:
AIM2 (absent in melanoma–2), ASCVD (atherosclerotic cardiovascular disease), BM (bone marrow), CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study), CHD (coronary heart disease), CHIP (clonal hematopoiesis of indeterminate potential), CI (confidence interval), FUSION (Finland–United States Investigation of NIDDM Genetics), HR (hazard ratio), HSC (hematopoietic stem cell), IL (interleukin), LDL (low-density lipoprotein), MGBB (Mass General Brigham Biobank), NLRP3 (nucleotide-binding oligomerization domain–like receptor family pyrin domain containing–3), OR (odds ratio), PAD (peripheral artery disease), UKBB (UK Biobank), VAF (variant allele frequency. Non-peer-reviewed references are indicated as #P, preprint and #A, abstract)To read this article in full you will need to make a payment
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References
- Predicting the 30-year risk of cardiovascular disease: the Framingham Heart Study.Circulation. 2009; 119: 3078-3084
- Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.Eur Heart J. 2017; 38: 2459-2472
- The intersection between aging and cardiovascular disease.Circ Res. 2012; 110: 1097-1108
- The changing landscape of atherosclerosis.Nature. 2021; 592: 524-533
- Inflammation and cardiovascular disease: from pathogenesis to therapeutic target.Curr Atheroscler Rep. 2014; 16: 1-7
- The origins of age-related proinflammatory state.Blood. 2005; 105: 2294-2299
- Inflammation, aging, and cardiovascular disease: JACC review topic of the week.J Am Coll Cardiol. 2022; 79: 837-847
- Aging of hematopoietic stem cells: DNA damage and mutations?.Exp Hematol. 2016; 44: 895-901
- Age-related clonal hematopoiesis.Blood. 2018; 131: 496-504
Busque L, Mio R, Mattioli J, et al. Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age. 1996.
MF Fey, S Liechti-Gallati, A von Rohr, et al, Clonality and X-inactivation patterns in hematopoietic cell populations detected by the highly informative M27 beta DNA probe. Blood, 83, 1994, 931–938.
- Acquired skewing of X-chromosome inactivation patterns in myeloid cells of the elderly suggests stochastic clonal loss with age.Br J Haematol. 1997; 98: 512-519
- Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes.Blood. 2015; 126: 9-16
- From FastQ data to high-confidence variant calls: the genome analysis toolkit best practices pipeline.Curr Protoc Bioinformatics. 2013; 43: 11.10.1-11.10.33
- Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples.Nat Biotechnol. 2013; 31: 213-219
- Discovery and characterization of artifactual mutations in deep coverage targeted capture sequencing data due to oxidative DNA damage during sample preparation.Nucleic Acids Res. 2013; 41 (-e): e67
- COSMIC: exploring the world’s knowledge of somatic mutations in human cancer.Nucleic Acids Res. 2015; 43: D805-D811
- Genetic variation in an individual human exome.PLoS Genet. 2008; 4e1000160
- Recurrent DNMT3A mutations in patients with myelodysplastic syndromes.Leukemia. 2011; 25: 1153-1158
- Age-related mutations associated with clonal hematopoietic expansion and malignancies.Nat Med. 2014; 20: 1472-1478
- Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.N Engl J Med. 2014; 371: 2477-2487
- Age-related clonal hematopoiesis associated with adverse outcomes.N Engl J Med. 2014; 371: 2488-2498
- Inherited causes of clonal hematopoiesis in 97,691 whole genomes.Nature. 2020; 586: 763-768
- Exome sequencing of 628,388 individuals identifies common and rare variant associations with clonal hematopoiesis phenotypes.medRxiv, 2022 (2021.12. 29.21268342)
- The JAK2 46/1 haplotype predisposes to MPL-mutated myeloproliferative neoplasms.Blood. 2010; 115: 4517-4523
- Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly.Blood. 2017; 130: 742-752
- Polygenic basis and biomedical consequences of telomere length variation.Nat Genet. 2021; 53: 1425-1433
- Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential.Sci Adv. 2022; 8: eabl6579
- Cancer therapy shapes the fitness landscape of clonal hematopoiesis.Nat Genet. 2020; 52: 1219-1226
- Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes.Cell Stem Cell. 2017; 21 (e4): 374-382
- Clonal myelopoiesis in the UK Biobank cohort: ASXL1 mutations are strongly associated with smoking.Leukemia. 2020; 34: 2660-2672
- Association of clonal hematopoiesis with chronic obstructive pulmonary disease.Blood. 2022; 139: 357-368
- Radioactive iodine–related clonal hematopoiesis in thyroid cancer is common and associated with decreased survival.J Clin Endocrinol Metab. 2018; 103: 4216-4223
- Genetics of smoking and risk of clonal hematopoiesis.Sci Rep. 2022; 12: 1-5
- Association of diet quality with prevalence of clonal hematopoiesis and adverse cardiovascular events.JAMA Cardiol. 2021; 6: 1069-1077
- Abstract P450: Radon is Associated With Clonal Hematopoiesis of Indeterminate Potential in the Women’s Health Initiative.Circulation. 2020; 141 (-AP): AP450
- Increased stem cell proliferation in atherosclerosis accelerates clonal hematopoiesis.Cell. 2021; 184 (e22): 1348-1361
- Premature menopause, clonal hematopoiesis, and coronary artery disease in postmenopausal women.Circulation. 2021; 143: 410-423
- Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling.Cell Stem Cell. 2021; 28 (e6): 1428-1442
- Infection makes micro-CHIPs into macro-CHIPs.Cell Stem Cell. 2021; 28: 1335-1336
- Increased prevalence of clonal hematopoiesis of indeterminate potential amongst people living with HIV.Sci Rep. 2022; 12: 1-7
- Clonal haematopoiesis is increased in early onset in systemic sclerosis.Rheumatology (Oxford). 2020; 59: 3499-3504
- Clonal hematopoiesis in patients with rheumatoid arthritis.Blood Cancer J. 2018; 8: 1-5
- Inflammatory cytokines promote clonal hematopoiesis with specific mutations in ulcerative colitis patients.Exp Hematol. 2019; 80 (e3): 36-41
- Obesity-Induced inflammation co-operates with Clonal Hematopoiesis of Indeterminate Potential (CHIP) mutants to promote leukemia development and cardiovascular disease.Blood. 2021; 138: 1094
- The roles of cholesterol and its metabolites in normal and malignant hematopoiesis.Front Endocrinol. 2019; 10: 204
- Hematopoiesis is regulated by cholesterol efflux pathways and lipid rafts: connections with cardiovascular diseases: Thematic Review Series: Biology of Lipid Rafts.J Lipid Res. 2020; 61: 667-675
- ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice.J Clin Invest. 2011; 121: 4138-4149
- ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation.Science. 2010; 328: 1689-1693
- Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease.N Engl J Med. 2017; 377: 111-121
- Clonal hematopoiesis associated with epigenetic aging and clinical outcomes.Aging Cell. 2021; 20: e13366
- TP53-mediated clonal hematopoiesis confers increased risk for incident peripheral artery disease.medRxiv, 2021
- Clonal hematopoiesis is associated with higher risk of stroke.Stroke. 2022; 29: 788-797
- Crucial role of hematopoietic JAK2 V617F in the development of aortic aneurysms.Haematologica. 2021; 106: 1910
- Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice.Science. 2017; 355: 842-847
- Macrophage inflammation, erythrophagocytosis, and accelerated atherosclerosis in Jak2 V617F mice.Circ Res. 2018; 123: e35-e47
- The AIM2 inflammasome exacerbates atherosclerosis in clonal haematopoiesis.Nature. 2021; 592: 296-301
- Association of clonal hematopoiesis with incident heart failure.J Am Coll Cardiol. 2021; 78: 42-52
- Somatic mosaicism in blood cells is a risk factor for incident heart failure in 200,628 UK biobank participants.Circulation. 2021; 144 (-A): A12798
- Association of mutations contributing to clonal hematopoiesis with prognosis in chronic ischemic heart failure.JAMA Cardiol. 2019; 4: 25-33
- Clonal hematopoiesis and risk of progression of heart failure with reduced left ventricular ejection fraction.J Am Coll Cardiol. 2021; 77: 1747-1759
- Multiple somatic mutations for clonal hematopoiesis are associated with increased mortality in patients with chronic heart failure.Circ Genom Precis Med. 2020; 13e003003
- Tet2-mediated clonal hematopoiesis accelerates heart failure through a mechanism involving the IL-1β/NLRP3 inflammasome.J Am Coll Cardiol. 2018; 71: 875-886
- Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction.JCI insight. 2020; 5 (-e): e135204
- CRISPR-mediated gene editing to assess the roles of Tet2 and Dnmt3a in clonal hematopoiesis and cardiovascular disease.Circ Res. 2018; 123: 335-341
- JAK2V617F-mediated clonal hematopoiesis accelerates pathological remodeling in murine heart failure.JACC Basic Transl Sci. 2019; 4: 684-697
- The cancer therapy-related clonal hematopoiesis driver gene Ppm1d promotes inflammation and non-ischemic heart failure in mice.Circ Res. 2021; 129: 684-698
- TP53-mediated therapy-related clonal hematopoiesis contributes to doxorubicin-induced cardiomyopathy by augmenting a neutrophil-mediated cytotoxic response.JCI Insight. 2021; 6 (-e): e146076
- Is hematopoietic clonality of indetermined potential a risk factor for pulmonary embolism?.TH Open. 2021; 5: e338-ee42
- Clonal hematopoiesis of indeterminate potential predicts incident venous thromboembolism in the UK biobank cohort.Circulation. 2021; 144 (-A): A12959
- Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms.Sci Transl Med. 2018; 10: eaan8292
- Prevalence and phenotypes of JAK2 V617F and calreticulin mutations in a Danish general population.Blood. 2019; 134: 469-479
- Clonal hematopoiesis with JAK2V617F promotes pulmonary hypertension with ALK1 upregulation in lung neutrophils.Nat Commun. 2021; 12: 1-18
- Clonal Hematopoiesis is Associated With Incident Severe Aortic Stenosis.Circulation. 2021; 144 (-A): A9334
- Clonal haematopoiesis in patients with degenerative aortic valve stenosis undergoing transcatheter aortic valve implantation.Eur Heart J. 2020; 41: 933-939
- Clonal Hematopoiesis of Indeterminate Potential: A Novel Risk Factor for Atrial Fibrillation in the UK Biobank Cohort.Circulation. 2021; 144 (-A): A12955
- Mechanisms and consequences of efferocytosis in advanced atherosclerosis.J Leukocyte Biol. 2009; 86: 1089-1095
- JAK2-V617F promotes venous thrombosis through β 1/β 2 integrin activation.J Clin Invest. 2018; 128: 4359-4371
- TET2-loss-of-function-driven clonal hematopoiesis exacerbates experimental insulin resistance in aging and obesity.Cell Rep. 2020; 33108326
- Somatic mutations in both blood cells and vascular endothelium from patients with severe coronary artery diseases.medRxiv, 2022
- Clonal hematopoietic mutations linked to platelet traits and the risk of thrombosis or bleeding.Haematologica. 2020; 105: 2020-2031
- Association of clonal hematopoiesis of indeterminate potential with worse kidney function and anemia in two cohorts of patients with advanced chronic kidney disease.J Am Soc Nephrol. 2022; 33: 985-995
- Antiinflammatory therapy with canakinumab for atherosclerotic disease.N Engl J Med. 2017; 377: 1119-1131
- TET2-Driven clonal hematopoiesis and response to canakinumab: An exploratory analysis of the CANTOS randomized clinical trial.JAMA Cardiol. 2022; 7: 521-528
- Anti-inflammatory therapy with canakinumab for the prevention of hospitalization for heart failure.Circulation. 2019; 139: 1289-1299
- Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies.Lancet North Am Ed. 2012; 379: 1205-1213
- Genetic interleukin 6 signaling deficiency attenuates cardiovascular risk in clonal hematopoiesis.Circulation. 2020; 141: 124-131
- Inhibiting Jak2 Ameliorates Pulmonary Hypertension: Fulfilling the Promise of Precision Medicine.Am J Respir Cell Mol Biol. 2021; 64: 12-13
- Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults.Nat Commun. 2016; 7: 1-7
Article info
Publication history
Published online: September 02, 2022
Accepted:
August 27,
2022
Received in revised form:
August 25,
2022
Received:
August 3,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Elsevier Inc. All rights reserved.
