Blood Protein Signatures Reveal How Clonal Hematopoiesis Drives Disease Risk
Large-scale proteomics uncovers distinct plasma protein patterns linked to DNMT3A, TET2, and other CH mutations, illuminating inflammatory pathways.
Summary
Clonal hematopoiesis (CH) — the age-related expansion of mutant blood stem cell clones — raises risks for cardiovascular disease and cancer, yet its systemic molecular effects remain poorly understood. This study used large-scale plasma proteomics across multiple population cohorts to map the protein signatures associated with CH mutations in genes including DNMT3A, TET2, ASXL1, and JAK2. Researchers identified dozens of differentially expressed plasma proteins, many involved in inflammation, immune regulation, and coagulation. Gene-specific proteomic profiles were distinct, suggesting different mechanistic pathways. Key inflammatory proteins such as IL-6 signaling mediators were elevated in TET2 and ASXL1 carriers. These findings provide a molecular framework linking CH mutations to downstream organ dysfunction and may help identify biomarkers or therapeutic targets for CH-associated diseases.
Detailed Summary
Clonal hematopoiesis (CH) occurs when somatic mutations in blood stem cells confer a competitive advantage, leading to clonal expansion detectable in a significant fraction of older adults. CH is associated with increased risks of hematologic malignancy, cardiovascular disease, and all-cause mortality, but the systemic biological changes it induces — particularly at the protein level circulating in blood — have not been comprehensively characterized.
This study leveraged large-scale aptamer-based plasma proteomics (SomaScan) measured in participants from multiple population-based cohorts, including the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and the Atherosclerosis Risk in Communities (ARIC) study. CH mutations were identified through whole-genome or whole-exome sequencing. Proteome-wide association analyses tested the relationship between CH driver mutations — primarily DNMT3A, TET2, ASXL1, and JAK2 V617F — and levels of thousands of plasma proteins, adjusting for age, sex, ancestry, and other covariates.
The investigators identified dozens of plasma proteins significantly associated with overall CH and with specific CH gene mutations. TET2 and ASXL1 mutations were associated with upregulation of proteins in inflammatory pathways, including mediators linked to IL-6 and NF-κB signaling — consistent with prior mechanistic studies implicating these pathways in CH-driven cardiovascular risk. DNMT3A mutations showed a partially distinct proteomic signature, with some shared and some unique protein associations. JAK2 V617F was associated with a particularly striking proteomic profile enriched for coagulation and myeloproliferative-related proteins, consistent with its known biology.
Pathway enrichment analyses confirmed that CH-associated proteins cluster in immune activation, inflammatory signaling, and hematopoietic regulation networks. Several proteins associated with CH have established roles in atherosclerosis and heart failure, providing a potential molecular bridge between CH and its clinical cardiovascular consequences. The study also identified proteins that mediate associations between CH and downstream disease outcomes, suggesting possible mechanistic intermediaries.
These findings are important for several reasons. First, they provide the most comprehensive plasma proteomic map of CH to date, spanning multiple mutations and cohorts. Second, the gene-specific signatures suggest that different CH driver mutations operate through distinct — though sometimes overlapping — inflammatory and coagulation mechanisms. Third, the identified proteins represent candidate biomarkers for detecting or monitoring CH-related disease progression, and some may be druggable targets. Caveats include the cross-sectional design limiting causal inference, the observational nature of cohort data, and the possibility that some protein changes may reflect consequences of subclinical disease rather than direct CH effects.
Key Findings
- TET2 and ASXL1 CH mutations are linked to elevated plasma proteins in IL-6 and NF-κB inflammatory pathways.
- JAK2 V617F shows a distinct proteomic signature enriched for coagulation and myeloproliferative-related proteins.
- DNMT3A mutations exhibit a partially unique proteomic profile compared to other CH driver genes.
- CH-associated proteins cluster in immune activation, inflammation, and hematopoietic regulation pathways.
- Several identified proteins may serve as biomarkers or therapeutic targets for CH-driven cardiovascular disease.
Methodology
Large-scale aptamer-based plasma proteomics (SomaScan) was performed in participants from TOPMed and ARIC cohorts with CH mutations identified by whole-genome/exome sequencing. Proteome-wide association analyses tested thousands of proteins against CH driver mutations, adjusting for age, sex, ancestry, and relevant covariates.
Study Limitations
The cross-sectional design prevents causal inference between CH mutations and protein changes. Protein associations may partly reflect subclinical disease rather than direct CH effects. Cohort-based observational data cannot fully exclude confounding from age-related comorbidities prevalent in CH carriers.
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