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