Increased prevalence of clonal hematopoiesis of indeterminate potential in hospitalized patients with COVID-19

Schenz, Judith; Rump, Katharina; Siegler, Benedikt Hermann; Hemmerling, Inga; Rahmel, Tim; Thon, Jan N.; Nowak, Hartmuth; Fischer, Dania; Hafner, Anna; Tichy, Lucas; Bomans, Katharina; Meggendorfer, Manja; Koos, Björn; Groote, Thilo von; Zarbock, Alexander; Fiedler, Mascha O.; Zemva, Johanna; Larmann, Jan; Merle, Uta; Adamzik, Michael; Müller‐Tidow, Carsten; Haferlach, Torsten; Leuschner, Florian; Weigand, Markus

doi:10.3389/fimmu.2022.968778

Cited by 8 publications

(8 citation statements)

References 43 publications

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“…Table S4: Clonal Hematopoiesis of Indeterminate Potential (CHIP) Genes and DNA methylation (DNAm) Genes CHIP genes were compiled from Schenz et al 27 and Hagiwara et al 34 DNAm genes were compiled from Rasmussen & Helin 57 and Ginno et al 58 These genes were used for our analysis of CHIP genes and DNAm gene variants respectively.…”

Section: Table S3: Sequencing Coveragementioning

confidence: 99%

“…Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by somatic mutations in leukemia-related “CHIP” genes detected in the blood of individuals without apparent hematologic malignancy 26,27 . The definition of CHIP has been a subject of ongoing discussion, ranging from a benign precursor state for hematologic neoplasms 28 , to the presence of a clonally expanded hematopoietic stem cell with a mutation with leukemogenic potential 29 .…”

Section: Introductionmentioning

confidence: 99%

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Increased Frequency of Clonal Hematopoiesis of Indeterminate Potential in Bloom Syndrome Probands and Carriers

Lin,

Wei,

Gebo

et al. 2024

Preprint

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Bloom Syndrome (BSyn) is an autosomal recessive disorder caused by biallelic germline variants in BLM, which functions to maintain genomic stability. BSyn patients have poor growth, immune defects, insulin resistance, and a significantly increased risk of malignancies, most commonly hematologic. The malignancy risk in carriers of pathogenic variants in BLM (BLM variant carriers) remains understudied. Clonal hematopoiesis of indeterminate potential (CHIP) is defined by presence of somatic mutations in leukemia-related genes in blood of individuals without leukemia and is associated with increased risk of leukemia. We hypothesize that somatic mutations driving clonal expansion may be an underlying mechanism leading to increased cancer risk in BSyn patients and BLM variant carriers. To determine whether de novo or somatic variation is increased in BSyn patients or carriers, we performed and analyzed exome sequencing on BSyn and control trios. We discovered that both BSyn patients and carriers had increased numbers of low-frequency, putative somatic variants in CHIP genes compared to controls. Furthermore, BLM variant carriers had increased numbers of somatic variants in DNA methylation genes compared to controls. There was no statistical difference in the numbers of de novo variants in BSyn probands compared to control probands. Our findings of increased CHIP in BSyn probands and carriers suggest that one or two germline pathogenic variants in BLM could be sufficient to increase the risk of clonal hematopoiesis. These findings warrant further studies in larger cohorts to determine the significance of CHIP as a potential biomarker of aging, cancer, cardiovascular disease, morbidity and mortality.

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Section: Table S3: Sequencing Coveragementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Increased Frequency of Clonal Hematopoiesis of Indeterminate Potential in Bloom Syndrome Probands and Carriers

Lin,

Wei,

Gebo

et al. 2024

Preprint

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“…Choi et al (60) observed a unique IFN-γ signature in severe COVID-19 patients with CH, which was partly explained by CH-dependent epigenetic alterations in classical (proinflammatory) monocytes. Furthermore, Schenz et al (61) provide evidence that CH exacerbates lymphoid and myeloid alterations in severe COVID-19. They found these associations to be age-dependent, as CH-associated lymphoid alterations were more prominent among individuals under 60 years old, whereas myeloid alterations were enhanced in the above-60 age group with CH (61).…”

Section: Clonal Hematopoiesis May Influence Inflammation In Covid-19mentioning

confidence: 99%

“…Furthermore, Schenz et al (61) provide evidence that CH exacerbates lymphoid and myeloid alterations in severe COVID-19. They found these associations to be age-dependent, as CH-associated lymphoid alterations were more prominent among individuals under 60 years old, whereas myeloid alterations were enhanced in the above-60 age group with CH (61). Whether these effects influence COVID-19 outcomes has yet to be determined, but based on these observations, further exploration is warranted.…”

Section: Clonal Hematopoiesis May Influence Inflammation In Covid-19mentioning

confidence: 99%

COVID-19 and the Genetics of Inflammation

Choudhri

Maslove

Rauh

2023

Critical Care Medicine

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COVID-19 and the Genetics of InflammationOBJECTIVE: Interindividual variability in the clinical progression of COVID-19 may be explained by host genetics. Emerging literature supports a potential inherited predisposition to severe forms of COVID-19. Demographic and inflammatory characteristics of COVID-19 suggest that acquired hematologic mutations leading to clonal hematopoiesis (CH) may further increase vulnerability to adverse sequelae. This review summarizes the available literature examining genetic predispositions to severe COVID-19 and describes how these findings could eventually be used to improve its clinical management.DATA SOURCES: A PubMed literature search was performed. STUDY SELECTION:Studies examining the significance of inherited genetic variation or acquired CH mutations in severe COVID-19 were selected for inclusion. DATA EXTRACTION:Relevant genetic association data and aspects of study design were qualitatively assessed and narratively synthesized.DATA SYNTHESIS: Genetic variants affecting inflammatory responses may increase susceptibility to severe COVID-19. Genome-wide association studies and candidate gene approaches have identified a list of inherited mutations, which likely alter cytokine and interferon secretion, and lung-specific mechanisms of immunity in COVID-19. The potential role of CH in COVID-19 is more uncertain at present; however, the available evidence suggests that the various types of acquired mutations and their differential influence on immune cell function must be carefully considered. CONCLUSIONS:The current literature supports the hypothesis that host genetic factors affect vulnerability to severe COVID-19. Further research is required to confirm the full scope of relevant variants and the causal mechanisms underlying these associations. Clinical approaches, which consider the genetic basis of interindividual variability in COVID-19 and potentially other causes of critical illness, could optimize hospital resource allocation, predict responsiveness to treatment, identify more efficacious drug targets, and ultimately improve outcomes.

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“…By estimating the timing of clone initiation and subsequent growth rates of clones, we can characterize evolutionary mechanisms that underlie aging 8 and malignant progression [9][10][11][12] . In blood, for example, this evolutionary process is known as clonal hematopoiesis and has been associated with many aging-related disorders such as anemia 13 , impaired immunity 14,15 , and cardiovascular disease 16,17 , as well as progression to hematopoietic cancers 5,9,18 . Previous analyses found that somatic mutations conferring higher fitness, measured by clonal growth rate, lead to a higher risk of malignant transformation [19][20][21] .…”

Section: Introductionmentioning

confidence: 99%

Estimating single cell clonal dynamics in human blood using coalescent theory

Johnson

Shuai

Schweinsberg

et al. 2023

Preprint

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While evolutionary approaches to medicine show promise, measuring evolution itself is difficult due to experimental constraints and the dynamic nature of body systems. In cancer evolution, continuous observation of clonal architecture is impossible, and longitudinal samples from multiple timepoints are rare. Increasingly available DNA sequencing datasets at single cell resolution enable the reconstruction of past evolution using mutational history, allowing for a better understanding of dynamics prior to detectable disease. We derive methods based on coalescent theory for estimating the net growth rate of clones from either reconstructed phylogenies or the number of shared mutations. Using single-cell datasets from blood, we apply and validate our analytical methods for estimating the net growth rate of hematopoietic clones, eliminating the need for complex simulations. We show that our estimates may have broad applications to improve mechanistic understanding and prognostic ability. Compared to clones with a single or unknown driver mutation, clones with multiple drivers have significantly increased growth rates (median 0.94 vs. 0.25 per year; p = 1.6 x 10-6). Further, stratifying patients with a myeloproliferative neoplasm (MPN) by the growth rate of their fittest clone shows that higher growth rates are associated with shorter time from clone initiation to MPN diagnosis (median 13.9 vs. 26.4 months; p = 0.0026)

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Increased prevalence of clonal hematopoiesis of indeterminate potential in hospitalized patients with COVID-19

Cited by 8 publications

References 43 publications

Increased Frequency of Clonal Hematopoiesis of Indeterminate Potential in Bloom Syndrome Probands and Carriers

Increased Frequency of Clonal Hematopoiesis of Indeterminate Potential in Bloom Syndrome Probands and Carriers

COVID-19 and the Genetics of Inflammation

Estimating single cell clonal dynamics in human blood using coalescent theory

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