Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Clonal haematopoiesis: connecting ageing and inflammation in cardiovascular disease

Nature Reviews Cardiology volume 17, pages 137–144 (2020)Cite this article

Subjects

An Author Correction to this article was published on 02 July 2020

This article has been updated

Abstract

Ageing and inflammation strongly drive the risk of cardiovascular disease. Work over the past decade has uncovered a common condition characterized by the positive selection of certain somatic mutations in haematopoietic stem cells in ageing humans. This phenomenon, known as clonal haematopoiesis of indeterminate potential (CHIP), occurs most commonly as a result of mutations in the transcriptional regulators DNMT3A, TET2 and ASXL1. CHIP is associated with a variety of adverse outcomes, including haematological cancer and death. Surprisingly, CHIP is also associated with a doubling of the risk of atherosclerotic cardiovascular disease. Studies in mice support the causality of this relationship. Mutations in TET2, which are among the most commonly found mutations in CHIP, lead to increased expression of inflammatory genes in innate immune cells, potentially explaining the link between mutations and increased cardiovascular risk. Therapies targeting the mutant clones or the increased inflammatory mediators might be useful for ameliorating the risk of cardiovascular disease. We propose that the mutations leading to clonal haematopoiesis contribute to the increased inflammation seen in ageing and thereby explain some of the age-related risk of cardiovascular disease.

Key points

  • Clonal haematopoiesis of indeterminate potential (CHIP) is a common age-related condition characterized by the clonal expansion of haematopoietic stem cells bearing mutations in certain genes, especially DNMT3A, TET2 and ASXL1.

  • CHIP is associated with increased risk of haematological malignancies and all-cause mortality, but also increased risk of atherosclerotic cardiovascular disease, venous thrombosis and worse outcomes in heart failure.

  • Mutations associated with CHIP seem to have effects on immune effector cells, such as macrophages and neutrophils, which might account for the increased risk of cardiovascular complications in individuals with CHIP.

  • No treatments are currently available to lower the risk of cardiovascular disease in those with CHIP, but blockade of inflammatory molecules is a potential strategy to mitigate the effects of CHIP.

  • Individuals incidentally found to have CHIP should undergo evaluation for lifestyle modifications to reduce the risk of cardiovascular disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Cardiovascular conditions related to CHIP-associated mutations.
Fig. 2: Mutational spectrum and prevalence of clonal haematopoiesis.

Similar content being viewed by others

Change history

References

  1. Wang, T. J. et al. Multiple biomarkers for the prediction of first major cardiovascular events and death. N. Engl. J. Med. 355, 2631–2639 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Pencina, M. J., D’Agostino, R. B. Sr, Larson, M. G., Massaro, J. M. & Vasan, R. S. Predicting the 30-year risk of cardiovascular disease: the Framingham Heart Study. Circulation 119, 3078–3084 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Sniderman, A. D. & Furberg, C. D. Age as a modifiable risk factor for cardiovascular disease. Lancet 371, 1547–1549 (2008).

    Article  PubMed  Google Scholar 

  4. Lloyd-Jones, D. M. et al. Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age. Circulation 113, 791–798 (2006).

    Article  PubMed  Google Scholar 

  5. Libby, P., Nahrendorf, M. & Swirski, F. K. Leukocytes link local and systemic inflammation in ischemic cardiovascular disease: an expanded “cardiovascular continuum”. J. Am. Coll. Cardiol. 67, 1091–1103 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).

    Article  CAS  PubMed  Google Scholar 

  7. Wikby, A. et al. The immune risk phenotype is associated with IL-6 in the terminal decline stage: findings from the Swedish NONA immune longitudinal study of very late life functioning. Mech. Ageing Dev. 127, 695–704 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Ferrucci, L. et al. The origins of age-related proinflammatory state. Blood 105, 2294–2299 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Furman, D. et al. Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states. Nat. Med. 23, 174–184 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Franceschi, C. & Campisi, J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J. Gerontol. A Biol. Sci. Med. Sci. 69 (Suppl. 1), 4–9 (2014).

    Google Scholar 

  11. Franceschi, C. et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N. Y. Acad. Sci. 908, 244–254 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Jaiswal, S. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488–2498 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Genovese, G. et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371, 2477–2487 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Xie, M. et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat. Med. 20, 1472–1478 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jaiswal, S. et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N. Engl. J. Med. 377, 111–121 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Zhang, Q. et al. Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature 525, 389–393 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Fuster, J. J. et al. Clonal hematopoiesis associated with Tet2 deficiency accelerates atherosclerosis development in mice. Science 355, 842–847 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Moore, K. J. et al. Macrophage trafficking, inflammatory resolution, and genomics in atherosclerosis: JACC Macrophage in CVD Series (Part 2). J. Am. Coll. Cardiol. 72, 2181–2197 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Schumski, A., Winter, C., Doring, Y. & Soehnlein, O. The ins and outs of myeloid cells in atherosclerosis. J. Innate Immun. 10, 479–486 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Doring, Y., Soehnlein, O. & Weber, C. Neutrophil extracellular traps in atherosclerosis and atherothrombosis. Circ. Res. 120, 736–743 (2017).

    Article  PubMed  CAS  Google Scholar 

  21. Franck, G. et al. Roles of PAD4 and NETosis in experimental atherosclerosis and arterial injury: implications for superficial erosion. Circ. Res. 123, 33–42 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ridker, P. M. A test in context: high-sensitivity C-reactive protein. J. Am. Coll. Cardiol. 67, 712–723 (2016).

    Article  PubMed  Google Scholar 

  23. Armitage, P. & Doll, R. A two-stage theory of carcinogenesis in relation to the age distribution of human cancer. Br. J. Cancer 11, 161–169 (1957).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Welch, J. S. et al. The origin and evolution of mutations in acute myeloid leukemia. Cell 150, 264–278 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Martincorena, I. & Campbell, P. J. Somatic mutation in cancer and normal cells. Science 349, 1483–1489 (2015).

    Article  CAS  PubMed  Google Scholar 

  26. Abkowitz, J. L., Catlin, S. N., McCallie, M. T. & Guttorp, P. Evidence that the number of hematopoietic stem cells per animal is conserved in mammals. Blood 100, 2665–2667 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Lee-Six, H. et al. Population dynamics of normal human blood inferred from somatic mutations. Nature 561, 473–478 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nowell, P. C. The minute chromosome (Phl) in chronic granulocytic leukemia. Blut 8, 65–66 (1962).

    Article  CAS  PubMed  Google Scholar 

  29. Rowley, J. D. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243, 290–293 (1973).

    Article  CAS  PubMed  Google Scholar 

  30. Nowell, P. C. The clonal evolution of tumor cell populations. Science 194, 23–28 (1976).

    Article  CAS  PubMed  Google Scholar 

  31. Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Fey, M. F. et al. Clonality and X-inactivation patterns in hematopoietic cell populations detected by the highly informative M27 beta DNA probe. Blood 83, 931–938 (1994).

    Article  CAS  PubMed  Google Scholar 

  33. Busque, L. et al. Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age. Blood 88, 59–65 (1996).

    Article  CAS  PubMed  Google Scholar 

  34. Champion, K. M., Gilbert, J. G., Asimakopoulos, F. A., Hinshelwood, S. & Green, A. R. Clonal haemopoiesis in normal elderly women: implications for the myeloproliferative disorders and myelodysplastic syndromes. Br J. Haematol. 97, 920–926 (1997).

    Article  CAS  PubMed  Google Scholar 

  35. Busque, L. et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat. Genet. 44, 1179–1181 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sperling, A. S., Gibson, C. J. & Ebert, B. L. The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia. Nat. Rev. Cancer 17, 5–19 (2017).

    Article  CAS  PubMed  Google Scholar 

  37. Jan, M., Ebert, B. L. & Jaiswal, S. Clonal hematopoiesis. Semin. Hematol. 54, 43–50 (2017).

    Article  PubMed  Google Scholar 

  38. Bowman, R. L., Busque, L. & Levine, R. L. Clonal hematopoiesis and evolution to hematopoietic malignancies. Cell Stem Cell 22, 157–170 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. McKerrell, T. et al. Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. Cell Rep. 10, 1239–1245 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Acuna-Hidalgo, R. et al. Ultra-sensitive sequencing identifies high prevalence of clonal hematopoiesis-associated mutations throughout adult life. Am. J. Hum. Genet. 101, 50–64 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Coombs, C. C. et al. Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes. Cell Stem Cell 21, 374–382.e4 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Young, A. L., Challen, G. A., Birmann, B. M. & Druley, T. E. Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat. Commun. 7, 12484 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gibson, C. J. et al. Clonal hematopoiesis associated with adverse outcomes after autologous stem-cell transplantation for lymphoma. J. Clin. Oncol. 35, 1598–1605 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zink, F. et al. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 130, 742–752 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Buscarlet, M. et al. DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood 130, 753–762 (2017).

    Article  CAS  PubMed  Google Scholar 

  46. Abelson, S. et al. Prediction of acute myeloid leukaemia risk in healthy individuals. Nature 559, 400–404 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Steensma, D. P. et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 126, 9–16 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Desai, P. et al. Somatic mutations precede acute myeloid leukemia years before diagnosis. Nat. Med. 24, 1015–1023 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sellar, R. S., Jaiswal, S. & Ebert, B. L. Predicting progression to AML. Nat. Med. 24, 904–906 (2018).

    Article  CAS  PubMed  Google Scholar 

  50. Tonelli, M. et al. Relation between red blood cell distribution width and cardiovascular event rate in people with coronary disease. Circulation 117, 163–168 (2008).

    Article  PubMed  Google Scholar 

  51. Patel, K. V., Ferrucci, L., Ershler, W. B., Longo, D. L. & Guralnik, J. M. Red blood cell distribution width and the risk of death in middle-aged and older adults. Arch. Intern. Med. 169, 515–523 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Perlstein, T. S., Weuve, J., Pfeffer, M. A. & Beckman, J. A. Red blood cell distribution width and mortality risk in a community-based prospective cohort. Arch. Intern. Med. 169, 588–594 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Lippi, G. et al. Relation between red blood cell distribution width and inflammatory biomarkers in a large cohort of unselected outpatients. Arch. Pathol. Lab. Med. 133, 628–632 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. Gerszten, R. E. et al. MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature 398, 718–723 (1999).

    Article  CAS  PubMed  Google Scholar 

  55. Dorsheimer, L. et al. Association of mutations contributing to clonal hematopoiesis with prognosis in chronic ischemic heart failure. JAMA Cardiol. 4, 25–33 (2019).

    Article  PubMed  Google Scholar 

  56. Morgan, K. J. & Gilliland, D. G. A role for JAK2 mutations in myeloproliferative diseases. Annu. Rev. Med. 59, 213–222 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Marchioli, R. et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J. Clin. Oncol. 23, 2224–2232 (2005).

    Article  PubMed  Google Scholar 

  58. Hinds, D. A. et al. Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms. Blood 128, 1121–1128 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Carobbio, A. et al. Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and Jak2 mutation status. Blood 109, 2310–2313 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Landolfi, R. et al. Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera. Blood 109, 2446–2452 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Wolach, O. et al. Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms. Sci. Transl Med. 10, eaan8292 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Sano, S. et al. Tet2-mediated clonal hematopoiesis accelerates heart failure through a mechanism involving the IL-1β/NLRP3 inflammasome. J. Am. Coll. Cardiol. 71, 875–886 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Sano, S. et al. CRISPR-mediated gene editing to assess the roles of Tet2 and Dnmt3a in clonal hematopoiesis and cardiovascular disease. Circ. Res. 123, 335–341 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Wang, W. et al. Macrophage inflammation, erythrophagocytosis, and accelerated atherosclerosis in Jak2 (V617F) mice. Circ. Res. 123, e35–e47 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Liu, D. J. et al. Exome-wide association study of plasma lipids in >300,000 individuals. Nat. Genet. 49, 1758–1766 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. van Vlijmen, B. J. et al. Macrophage p53 deficiency leads to enhanced atherosclerosis in APOE*3-Leiden transgenic mice. Circ. Res. 88, 780–786 (2001).

    Article  PubMed  Google Scholar 

  67. Merched, A. J., Williams, E. & Chan, L. Macrophage-specific p53 expression plays a crucial role in atherosclerosis development and plaque remodeling. Arterioscler. Thromb. Vasc. Biol. 23, 1608–1614 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Svensson, E. C. et al. TET2-driven clonal hematopoiesis predicts enhanced response to canakinumab in the CANTOS trial: an exploratory analysis [abstract 15111]. Circulation 138 (Suppl. 1), A15111 (2018).

    Google Scholar 

  69. Leoni, C. et al. Dnmt3a restrains mast cell inflammatory responses. Proc. Natl. Acad. Sci. USA 114, E1490–E1499 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Coombs, C. C. et al. Identification of clonal hematopoiesis mutations in solid tumor patients undergoing unpaired next-generation sequencing assays. Clin. Cancer Res. 24, 5918–5924 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Guryanova, O. A. et al. Dnmt3a regulates myeloproliferation and liver-specific expansion of hematopoietic stem and progenitor cells. Leukemia 30, 1133–1142 (2016).

    Article  CAS  PubMed  Google Scholar 

  72. Cole, C. B. et al. Haploinsufficiency for DNA methyltransferase 3A predisposes hematopoietic cells to myeloid malignancies. J. Clin. Invest. 127, 3657–3674 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Abdel-Wahab, O. et al. Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo. J. Exp. Med. 210, 2641–2659 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Obeng, E. A. et al. Physiologic expression of Sf3b1(K700E) causes impaired erythropoiesis, aberrant splicing, and sensitivity to therapeutic spliceosome modulation. Cancer Cell 30, 404–417 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Shirai, C. L. et al. Mutant U2AF1 expression alters hematopoiesis and pre-mRNA splicing in vivo. Cancer Cell 27, 631–643 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kim, E. et al. SRSF2 mutations contribute to myelodysplasia by mutant-specific effects on exon recognition. Cancer Cell 27, 617–630 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Sun, B. et al. Phosphatase Wip1 negatively regulates neutrophil migration and inflammation. J. Immunol. 192, 1184–1195 (2014).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors were supported by Burroughs Wellcome Fund Career Award for Medical Scientists and Fondation Leducq Transatlantic Network of Excellence (S.J.) and by the National Heart, Lung, and Blood Institute (R01HL080472), AHA (18CSA34080399) and the RRM Charitable Fund (P.L.).

Author information

Authors and Affiliations

  1. Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, USA

    Siddhartha Jaiswal

  2. Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Peter Libby

Authors
  1. Siddhartha Jaiswal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter Libby
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Both authors wrote the manuscript, and reviewed and edited it before submission.

Corresponding author

Correspondence to Siddhartha Jaiswal.

Ethics declarations

Competing interests

S.J. has filed patents related to the topic of this Review and is a consultant for GRAIL. P.L. is an unpaid consultant to, or is involved in clinical trials for, Amgen, AstraZeneca, Esperion Therapeutics, Ionis Pharmaceuticals, Kowa Pharmaceuticals, Novartis, Pfizer, Sanofi-Regeneron and XBiotech. P.L. is a member of the scientific advisory board for Amgen, Corvidia Therapeutics, DalCor Pharmaceuticals, IFM Therapeutics, Kowa Pharmaceuticals, Medimmune, Novartis, Olatec Therapeutics and XBiotech. P.L. has a financial interest in XBiotech, a company developing therapeutic human antibodies. P.L.’s interests were reviewed and are managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict of interest policies.

Additional information

Peer review information

Nature Reviews Cardiology thanks F. Swirski and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jaiswal, S., Libby, P. Clonal haematopoiesis: connecting ageing and inflammation in cardiovascular disease. Nat Rev Cardiol 17, 137–144 (2020). https://doi.org/10.1038/s41569-019-0247-5

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41569-019-0247-5

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing