Clonal haematopoiesis and dysregulation of the immune system

Belizaire, Roger; Wong, Waihay J.; Robinette, Michelle L.; Ebert, Benjamin L.

doi:10.1038/s41577-023-00843-3

Cited by 35 publications

(19 citation statements)

References 233 publications

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“…Notably, studies in mice and zebrafish support a positive feedback loop between CH expansion and inflammation, where CH promotes inflammation, and the relative fitness and resistance to inflammation of CH clones further fuel clonal expansion, creating a vicious cycle of inflammation and expansion [31][32][33] . These findings highlight the complexity of the interactions between exposome, inherited, and somatic genomes, shedding light on the pathogenesis of CH in the context of (inflamm-)aging [34][35][36] . Further research is crucial to fully unravel these intricate relationships' underlying mechanisms and potential therapeutic implications.…”

Section: Discussionmentioning

confidence: 78%

Long-term longitudinal analysis of 4,187 participants reveals new insights into determinants of incident clonal hematopoiesis

Uddin,

Saadatagah,

Niroula

et al. 2023

Preprint

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Clonal hematopoiesis (CH), characterized by blood cells predominantly originating from a single mutated hematopoietic stem cell, is linked to diverse aging-related diseases, including hematologic malignancy and atherosclerotic cardiovascular disease (ASCVD). While CH is common among older adults, the underlying factors driving its development are largely unknown. To address this, we performed whole-exome sequencing on 8,374 blood DNA samples collected from 4,187 Atherosclerosis Risk in Communities Study (ARIC) participants over a median follow-up of 21 years. During this period, 735 participants developed incident CH. We found that age at baseline, sex, and dyslipidemia significantly influence the incidence of CH, while ASCVD and other traditional risk factors for ASCVD did not exhibit such associations. Our study also revealed associations between germline genetic variants and incident CH, prioritizing genes in CH development. Our comprehensive longitudinal assessment yields novel insights into the factors contributing to incident CH in older adults.

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Section: Discussionmentioning

confidence: 78%

Long-term longitudinal analysis of 4,187 participants reveals new insights into determinants of incident clonal hematopoiesis

Uddin,

Saadatagah,

Niroula

et al. 2023

Preprint

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“…3 The intersection of pathogenic germline affecting telomere function and DNA damage response, along with clonal haematopoiesis, bone marrow failure syndromes, autoimmunity and refractory cytopenias, is an area of active investigation. 4 GOF somatic variants in STAT3 and clonal T-cell populations have been associated with refractory cyclical thrombocytopenia (which arguably can be viewed as a form of chronic dysregulated thrombopoiesis with thrombocytopenia alternating with thrombocytosis) in two patients. 5 These variants are also associated with large granular lymphocyte disease (LGL), autoimmunity and cytopenias.…”

Section: Somatic (Acquired) Associations With Immune Thrombocytopeniamentioning

confidence: 99%

“…Mutations associated with clonal haematopoiesis, most commonly in DNMT3A, ASXL1 and TET2, have been observed in association with rITP 3 . The intersection of pathogenic germline affecting telomere function and DNA damage response, along with clonal haematopoiesis, bone marrow failure syndromes, autoimmunity and refractory cytopenias, is an area of active investigation 4 …”

Section: Introductionmentioning

confidence: 99%

The role of genetics in refractory immune thrombocytopenia

Zehnder,

Bussel,

Cooper

2023

Br J Haematol

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SummaryPatients with refractory immune thrombocytopenia (rITP) have increased morbidity and mortality. Currently, there is limited understanding of the cause of refractoriness and no markers to help direct novel treatment options. Understanding the reason(s) for refractoriness is crucial to determining novel treatment options. The pathogenesis underlying rITP has generally been thought to be an underlying genetic predisposition with an environmental trigger. Familial ITP remains rare, and there are few twin studies, suggesting that a simple genetic cause is unlikely. However, genetic mutations provide the background for several autoimmune diseases. In this review, we explore the evidence of either an inherited genetic cause of rITP or an acquired mutation, in particular one resulting in clonal expansion of cytotoxic T cells.

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“…7 Along with increased risk of MN, patients with CHIP and CCUS have elevated mortality from ischemic cardiovascular disease and develop other age-associated inflammatory diseases. 8 Although risk of MN is known to be genotypedependent, genotype-specific risks for inflammatory diseases are emerging. 8 Mutations in the epigenetic modifier TET2 may confer a particular risk for inflammatory sequalae, as suggested by retrospective human data and preclinical mouse models that have linked Tet2-mutated CHIP and CCUS to ischemic cardiovascular disease, gout, chronic liver disease, and several other inflammatory diseases via myeloid activation.…”

Section: Introductionmentioning

confidence: 99%

“…8 Although risk of MN is known to be genotypedependent, genotype-specific risks for inflammatory diseases are emerging. 8 Mutations in the epigenetic modifier TET2 may confer a particular risk for inflammatory sequalae, as suggested by retrospective human data and preclinical mouse models that have linked Tet2-mutated CHIP and CCUS to ischemic cardiovascular disease, gout, chronic liver disease, and several other inflammatory diseases via myeloid activation. [8][9][10] Because of the shared associations of CH and GCA with older age and MN as well as mutual evidence of myeloid activation, we hypothesized that CHIP and CCUS would be associated with incident GCA.…”

Section: Introductionmentioning

confidence: 99%

Association of Somatic TET2 Mutations With Giant Cell Arteritis

Robinette,

Weeks,

Kramer

et al. 2024

Arthritis & Rheumatology

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ObjectiveGiant cell arteritis (GCA) is an age‐related vasculitis. Prior studies have identified an association between GCA and hematologic malignancies (HM). How the presence of somatic mutations which drive development of HM, or clonal hematopoiesis (CH), may influence clinical outcomes in GCA is not well understood.MethodsTo examine an association between CH and GCA, we analyzed sequenced exomes of 470960 UK Biobank participants for the presence of CH and used multivariable Cox regression. To examine the clinical phenotype of GCA in patients with and without somatic mutations across the spectrum of CH to HM, we performed targeted sequencing of blood samples and electronic health record review on 114 patients with GCA seen at our institution. We then examined associations between specific clonal mutations and GCA disease manifestations.ResultsUKB participants with CH had a 1.48‐fold increased risk of incident GCA compared to UKB participants without CH. GCA risk was highest among individuals with cytopenia (HR 2.98, p = 0.00178) and with TET2 mutation (HR 2.02, p = 0.00116). Mutations were detected in 27.2% of our institutional GCA cohort, 3 of whom had HM at GCA diagnosis. TET2 mutations were associated with vision loss in patients with GCA (OR 4.33, p = 0.047).ConclusionsCH increases risk for development of GCA in a genotype‐specific fashion, with greatest risk being conferred by the presence of mutations in TET2. Somatic TET2 mutations likewise increase the risk of GCA‐associated vision loss. Integration of somatic genetic testing in GCA diagnostics may be warranted in the future.This article is protected by copyright. All rights reserved.

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Clonal haematopoiesis and dysregulation of the immune system

Cited by 35 publications

References 233 publications

Long-term longitudinal analysis of 4,187 participants reveals new insights into determinants of incident clonal hematopoiesis

Long-term longitudinal analysis of 4,187 participants reveals new insights into determinants of incident clonal hematopoiesis

The role of genetics in refractory immune thrombocytopenia

Association of Somatic TET2 Mutations With Giant Cell Arteritis

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