DECONVOLUTION OF CLONAL HEMATOPOIESIS ASSOCIATED INFLAMMATION IN HEALTH AND DISEASE
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 发起方
- VASCage GmbH
- 入组人数
- 120
- 试验地点
- 1
- 主要终点
- Inflammatory transcriptional profile of mutation-bearing immune cells
研究概览
简要总结
Clonal hematopoiesis (CH), including clonal hematopoiesis of indeterminate potential (CHIP), is an age-associated condition characterized by the expansion of hematopoietic stem and progenitor cell clones carrying acquired somatic mutations. Although CH is associated with an increased risk of hematologic malignancies, its greater public health impact derives from its strong association with cardiovascular diseases, including coronary artery disease and stroke. Emerging evidence suggests that CH-associated mutations promote chronic inflammatory signaling in myeloid immune cells, thereby contributing to atherosclerosis and adverse cardiovascular remodeling.
This observational translational study aims to characterize the biological spectrum of clonal hematopoiesis across different stages of disease risk and manifestation. Using state-of-the-art single-cell and multi-omics approaches, the study will compare inflammatory pathways, immune cell states, and mutation-associated molecular programs among healthy individuals without CH, individuals with high-risk CH, and patients with CH-associated hematologic or cardiovascular disease. The ultimate goal is to identify shared and disease-specific mechanisms linking clonal hematopoiesis to adverse clinical outcomes and to generate insights for future preventive, anti-clonal, and anti-inflammatory therapeutic strategies.
详细描述
Background and Rationale:
Clonal hematopoiesis (CH), including clonal hematopoiesis of indeterminate potential (CHIP), arises from acquired somatic mutations in hematopoietic stem and progenitor cells that accumulate throughout life and drive clonal expansion. The most frequently affected genes include DNMT3A, TET2, and ASXL1. While such mutations are also involved in the pathogenesis of hematologic malignancies such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), progression to overt hematologic cancer occurs only in a minority of affected individuals.
In contrast, epidemiological studies have consistently demonstrated a strong association between clonal hematopoiesis and cardiovascular disease. Individuals carrying CHIP-associated mutations have a substantially increased risk of coronary artery disease, myocardial infarction, stroke, and cardiovascular mortality. The magnitude of risk conferred by CHIP has been reported to be comparable to established cardiovascular risk factors such as smoking or hypertension.
Experimental and mechanistic studies suggest that CH-associated mutations remodel immune-cell function through epigenetic reprogramming and activation of inflammatory pathways, including the NLRP3 inflammasome and cGAS-STING signaling. These alterations enhance the proliferation, activation, and inflammatory potential of myeloid immune cells, resulting in chronic sterile inflammation that can promote atherosclerosis, vascular injury, and adverse cardiac remodeling.
Importantly, clonal hematopoiesis is not considered a disease entity itself but rather a common biological state and independent risk factor for a range of age-related disorders. Since clonal hematopoiesis develops in varying degrees in a substantial proportion of the aging population, understanding its biological consequences represents a major opportunity for disease prevention.
研究设计
- 研究类型
- Observational
- 观察模型
- Case Control
- 时间视角
- Cross Sectional
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Participants must be ≥18 years of age and meet at least one of the following criteria:
- •Written informed consent has been obtained for participation in the study "Deconvolution of Clonal Hematopoiesis-Associated Inflammation in Health and Disease"; OR
- •Participant is enrolled in the Inn.Health study and has provided written informed consent; OR
- •Participant is enrolled in the study "Clonal Hematopoiesis of Indeterminate Potential and Infarct Severity in ST-Elevation Myocardial Infarction" and has provided written informed consent.
- •Group A: Control Group (n=20)
- •Age ≥60 years
- •No detectable somatic variant identified by peripheral blood next-generation sequencing (NGS)
- •No history of stroke or myocardial infarction
- •No surgery within the previous 3 months
- •No diagnosis of a WHO-defined neoplasm
- •No cytopenia at study enrollment Group B: Low-Risk Clonal Hematopoiesis Risk Score (CHRS) Group (n=20)
- •Age ≥60 years
- •Somatic variant in DNMT3A, TET2, ASXL1, or JAK2 with variant allele frequency (VAF) ≥2% in peripheral blood
- •No history of stroke or myocardial infarction
- •No surgery within the previous 3 months
- •No diagnosis of a WHO-defined neoplasm
- •No cytopenia at study enrollment
- •Low-risk CHRS (<9.5 points) Group C: Intermediate-/High-Risk CHRS Group (n=20)
- •Age ≥60 years
- •Somatic variant in DNMT3A, TET2, ASXL1, or JAK2 with VAF ≥2% in peripheral blood
- •No history of stroke or myocardial infarction
- •No surgery within the previous 3 months
- •No diagnosis of a WHO-defined neoplasm
- •No cytopenia at study enrollment
- •Intermediate- or high-risk CHRS (>9.5 points) Group D: Clonal Cytopenia of Undetermined Significance (CCUS) Group (n=20)
- •Age ≥60 years
- •Somatic variant in DNMT3A, TET2, ASXL1, or JAK2 with VAF ≥2% in peripheral blood
- •No history of stroke or myocardial infarction
- •No surgery within the previous 3 months
- •No diagnosis of a WHO-defined neoplasm
- •Untreated, unexplained cytopenia present for ≥4 months
- •Hemoglobin <13 g/dL (men) or <12 g/dL (women), and/or absolute neutrophil count <1.8 × 10⁹/L, and/or platelet count <150 × 10⁹/L
- •No diagnostic criteria for a defined myeloid neoplasm based on bone marrow examination Group E: Cardiovascular Disease Group (n=20)
- •Age ≥60 years
- •Somatic variant in DNMT3A, TET2, ASXL1, or JAK2 with VAF ≥2% in peripheral blood
- •ST-segment elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention (PCI) within the previous 4 months
- •No history of coronary artery bypass grafting (CABG)
- •No history of stroke
- •No cytopenia at study enrollment
- •No diagnosis of a WHO-defined neoplasm Group F: Low-Risk Myelodysplastic Syndrome (MDS) Group (n=20)
- •Age ≥60 years
- •Untreated, newly diagnosed (<3 months from diagnosis) low-risk myelodysplastic syndrome according to the Revised International Prognostic Scoring System (IPSS-R score >1.5 to 3.0)
- •No history of stroke or myocardial infarction
排除标准
- •Treatment with immunosuppressive medication within the previous 4 weeks, including but not limited to systemic corticosteroids, methotrexate, other disease-modifying antirheumatic drugs (DMARDs), colchicine, TNF-α inhibitors, mTOR inhibitors, calcineurin inhibitors, or immunomodulatory antibodies
- •History of rheumatologic, autoinflammatory, or autoimmune disease
研究组 & 干预措施
Group A: Healthy Controls
Participants aged ≥60 years without detectable clonal hematopoiesis-associated somatic variants, no history of myocardial infarction or stroke, no cytopenia, no WHO-defined neoplasm, and no major surgery within the previous 3 months.
Group B: Low-Risk Clonal Hematopoiesis
Participants aged ≥60 years with clonal hematopoiesis carrying a somatic mutation in DNMT3A, TET2, ASXL1, or JAK2 (variant allele frequency ≥2%), no prior cardiovascular events, no cytopenia, no WHO-defined neoplasm, and a low Clonal Hematopoiesis Risk Score (CHRS <9.5).
Group C: Intermediate-/High-Risk Clonal Hematopoiesis
Participants aged ≥60 years with clonal hematopoiesis carrying a somatic mutation in DNMT3A, TET2, ASXL1, or JAK2 (variant allele frequency ≥2%), no prior cardiovascular events, no cytopenia, no WHO-defined neoplasm, and an intermediate or high Clonal Hematopoiesis Risk Score (CHRS >9.5).
Group D: Clonal Cytopenia of Undetermined Significance (CCUS)
Participants aged ≥60 years with clonal hematopoiesis-associated mutations and persistent unexplained cytopenia for at least 4 months who do not meet diagnostic criteria for a myeloid neoplasm based on bone marrow evaluation.
Group E: Cardiovascular Disease (Post-STEMI)
Participants aged ≥60 years with clonal hematopoiesis-associated mutations and a recent ST-segment elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention within the previous 4 months, without prior stroke, coronary artery bypass graft surgery, cytopenia, or WHO-defined neoplasm.
Group F: Lower-Risk Myelodysplastic Syndrome (MDS)
Participants aged ≥60 years with newly diagnosed (<3 months), untreated lower-risk myelodysplastic syndrome defined by an IPSS-R score >1.5 to 3 points and no history of myocardial infarction or stroke.
结局指标
主要结局
Inflammatory transcriptional profile of mutation-bearing immune cells
时间窗: Baseline
Single-cell gene expression differences in predefined inflammatory pathways (including NLRP3 inflammasome, interferon signaling, and cGAS-STING-related pathways) between immune cells with and without clonal hematopoiesis-associated somatic variants and across study groups.
次要结局
未报告次要终点