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TET2 Mutant Clonal Hematopoiesis Enhances Severity of COVID-19 Related Cytokine Release Syndrome and is Associated with Increased Mortality

ABSTRACT: In this study we performed single-cell DNAseq + proteogenomics of PBMCs from COVID19 patients and patients with clonal hematopoiesis to identify the cell types that carry the mutations of interest.

ORGANISM(S): Homo sapiens

PROVIDER: GSE211379 | GEO | 2024/08/14

REPOSITORIES: GEO

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TET2 Mutant Clonal Hematopoiesis Enhances Severity of COVID-19 Related Cytokine Release Syndrome and is Associated with Increased Mortality [DNA-seq]

Project description:In this study we performed DNA Sequencing of PBMCs to identify mutations associated with clonal hematopoiesis in patients with COVID19 and non-COVID19 patients.

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TET2 Mutant Clonal Hematopoiesis Enhances Severity of COVID-19 Related Cytokine Release Syndrome and is Associated with Increased Mortality [scMULT]

Project description:Coronavirus disease 2019 (COVID-19) is associated with significant morbidity and mortality, albeit with considerable heterogeneity among affected individuals. Emerging evidence points towards an important role of preexisting host factors, such as a deregulated inflammatory response at the time of infection. Here, we demonstrate the negative impact of clonal hematopoiesis, a prevalent clonal disorder of ageing individuals, on COVID-19-related cytokine release severity and mortality. In this study we perform Multiome single cell sequencing of PBMCs from COVID19 patients and patients with clonal hematopoiesis.

2024-08-14 | GSE210432 | GEO

TET2 Mutant Clonal Hematopoiesis Enhances Severity of COVID-19 Related Cytokine Release Syndrome and is Associated with Increased Mortality [scRNA-seq]

Project description:Coronavirus disease 2019 (COVID-19) is associated with significant morbidity and mortality, albeit with considerable heterogeneity among affected individuals. Emerging evidence points towards an important role of preexisting host factors, such as a deregulated inflammatory response at the time of infection. Here, we demonstrate the negative impact of clonal hematopoiesis, a prevalent clonal disorder of ageing individuals, on COVID-19-related cytokine release severity and mortality. In this study we perform single cell RNA sequencing of PBMCs from COVID19 patients and patients with clonal hematopoiesis.

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TET2 Mutant Clonal Hematopoiesis Enhances Severity of COVID-19 Related Cytokine Release Syndrome and is Associated with Increased Mortality.

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-08-13 | GSE210435 | GEO

TET2-mutant clonal hematopoiesis and risk of gout.

Project description:Gout is a common inflammatory arthritis caused by precipitation of monosodium urate (MSU) crystals in individuals with hyperuricemia. Acute flares are accompanied by secretion of proinflammatory cytokines, including interleukin-1β (IL-1β). Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition predisposing to hematologic cancers and cardiovascular disease. CHIP is associated with elevated IL-1β, thus we investigated CHIP as a risk factor for gout. To test the clinical association between CHIP and gout, we analyzed whole exome sequencing data from 177 824 individuals in the MGB Biobank (MGBB) and UK Biobank (UKB). In both cohorts, the frequency of gout was higher among individuals with CHIP than without CHIP (MGBB, CHIP with variant allele fraction [VAF] ≥2%: odds ratio [OR], 1.69; 95% CI, 1.09-2.61; P = .0189; UKB, CHIP with VAF ≥10%: OR, 1.25; 95% CI, 1.05-1.50; P = .0133). Moreover, individuals with CHIP and a VAF ≥10% had an increased risk of incident gout (UKB: hazard ratio [HR], 1.28; 95% CI, 1.06-1.55; P = .0107). In murine models of gout pathogenesis, animals with Tet2 knockout hematopoietic cells had exaggerated IL-1β secretion and paw edema upon administration of MSU crystals. Tet2 knockout macrophages elaborated higher levels of IL-1β in response to MSU crystals in vitro, which was ameliorated through genetic and pharmacologic Nlrp3 inflammasome inhibition. These studies show that TET2-mutant CHIP is associated with an increased risk of gout in humans and that MSU crystals lead to elevated IL-1β levels in Tet2 knockout murine models. We identify CHIP as an amplifier of NLRP3-dependent inflammatory responses to MSU crystals in patients with gout.

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Aging drives Tet2+/- clonal hematopoiesis via IL-1 signaling.

Project description:Clonal hematopoiesis of indeterminate potential (CHIP), also referred to as aging-related clonal hematopoiesis, is defined as an asymptomatic clonal expansion of mutant mature hematopoietic cells in ≥4% of blood leukocytes. CHIP associates with advanced age and increased risk for hematological malignancy, cardiovascular disease, and all-cause mortality. Loss-of-function somatic mutations in TET2 are frequent drivers of CHIP. However, the contribution of aging-associated cooperating cell-extrinsic drivers, like inflammation, remains underexplored. Using bone marrow (BM) transplantation and newly developed genetic mosaicism (HSC-SCL-Cre-ERT; Tet2+/flox; R26+/tm6[CAG-ZsGreen1]Hze) mouse models of Tet2+/-driven CHIP, we observed an association between increased Tet2+/- clonal expansion and higher BM levels of the inflammatory cytokine interleukin-1 (IL-1) upon aging. Administration of IL-1 to mice carrying CHIP led to an IL-1 receptor 1 (IL-1R1)-dependent expansion of Tet2+/- hematopoietic stem and progenitor cells (HSPCs) and mature blood cells. This expansion was caused by increased Tet2+/- HSPC cell cycle progression, increased multilineage differentiation, and higher repopulation capacity compared with their wild-type counterparts. In agreement, IL-1α-treated Tet2+/- hematopoietic stem cells showed increased DNA replication and repair transcriptomic signatures and reduced susceptibility to IL-1α-mediated downregulation of self-renewal genes. More important, genetic deletion of IL-1R1 in Tet2+/- HPSCs or pharmacologic inhibition of IL-1 signaling impaired Tet2+/- clonal expansion, establishing the IL-1 pathway as a relevant and therapeutically targetable driver of Tet2+/- CHIP progression during aging.

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TET2 Mutant Clonal Hematopoiesis Enhances Severity of COVID-19 Related Cytokine Release Syndrome and is Associated with Increased Mortality

Project description:TET2 Mutant Clonal Hematopoiesis Enhances Severity of COVID-19 Related Cytokine Release Syndrome and is Associated with Increased Mortality

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TET2 Mutant Clonal Hematopoiesis Enhances Severity of COVID-19 Related Cytokine Release Syndrome and is Associated with Increased Mortality.

Project description:TET2 Mutant Clonal Hematopoiesis Enhances Severity of COVID-19 Related Cytokine Release Syndrome and is Associated with Increased Mortality.

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Parkinson's disease is associated with clonal hematopoiesis with TET2 mutation.

Project description:Clonal hematopoiesis of indeterminate potential (CHIP), a premalignant expansion of mutated hematopoietic stem cells, is linked to immune alterations. Given the role of neuroinflammation and immune dysfunction in Parkinson's disease (PD), we hypothesized a connection between CHIP and PD. We analyzed peripheral blood DNA from 341 PD, 92 isolated REM sleep behavior disorder (iRBD) patients, and 5003 controls using targeted sequencing of 24 genes associated with hematologic neoplasms. PD cases were classified by clinical progression mode: fast, slow, and typical. Using multivariable logistic regression models, CHIP prevalence was assessed against controls with a 1.0% variant allele fraction threshold. CHIP with TET2 mutations was more prevalent in PD than controls (aOR 1.75, 95% CI 1.11-2.77, p = 0.017), particularly in the fast motor progression subgroup (aOR 3.19, p = 0.004). No distinct associations were observed with iRBD. PD is linked to increased odds of CHIP with TET2 mutations, suggesting immune dysregulation in PD pathophysiology.

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TET2 Mutant Clonal Hematopoiesis Enhances Severity of COVID-19 Related Cytokine Release Syndrome and is Associated with Increased Mortality [scMULT]

Project description:TET2 Mutant Clonal Hematopoiesis Enhances Severity of COVID-19 Related Cytokine Release Syndrome and is Associated with Increased Mortality [scMULT]

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