Human plasma proteomic profile of clonal hematopoiesis
Plasma proteomic profiles associated with subclinical somatic mutations in blood cells may offer insights into downstream clinical consequences. Here we explore these patterns in clonal hematopoiesis of indeterminate potential (CHIP), which is linked to several cancer and non-cancer outcomes, including coronary artery disease (CAD). Among 61,833 participants (3881 with CHIP) from TOPMed and UK Biobank (UKB) with blood-based DNA sequencing and proteomic measurements (1,148 proteins by SomaScan in TOPMed and 2917 proteins by Olink in UKB), we identify 32 and 345 proteins from TOPMed and UKB, respectively, associated with CHIP and most prevalent driver genes (DNMT3A, TET2, and ASXL1). These associations show substantial heterogeneity by driver genes, sex, and race, and were enriched for immune response and inflammation pathways. Mendelian randomization in humans, coupled with ELISA in hematopoietic Tet2-/- vs wild-type mice validation, disentangle causal proteomic perturbations from TET2 CHIP. Lastly, we identify plasma proteins shared between CHIP and CAD.
Authors
- Michael Pan (ORCID: https://orcid.org/0009-0009-8529-897X)
- Bruce M. Psaty (ORCID: https://orcid.org/0000-0002-7278-2190)
- Vijay G. Sankaran (ORCID: https://orcid.org/0000-0003-0044-443X)
- Shamsudheen Karuthedath Vellarikkal (ORCID: https://orcid.org/0000-0002-6384-2948)
- Charles Kooperberg (ORCID: https://orcid.org/0000-0002-7986-8560)
- Ramachandran Srini Vasan (ORCID: https://orcid.org/0000-0001-7357-5970)
- Amélie Vromman (ORCID: https://orcid.org/0000-0002-1724-2095)
- Shi Fang
- Md Mesbah Uddin (ORCID: https://orcid.org/0000-0003-1846-0411)
- Alexander G. Bick (ORCID: https://orcid.org/0000-0001-5824-9595)
- Michael C. Honigberg (ORCID: https://orcid.org/0000-0001-8630-5021)
- Rajat M. Gupta (ORCID: https://orcid.org/0000-0001-9865-4106)
- Adolfo Correa (ORCID: https://orcid.org/0000-0002-9501-600X)
- Zhi Yu (ORCID: https://orcid.org/0000-0003-4810-3474)
- Bernhard Haring (ORCID: https://orcid.org/0000-0001-6109-431X)
- Art Schuermans (ORCID: https://orcid.org/0000-0001-8146-9692)
- Abhishek Niroula (ORCID: https://orcid.org/0000-0002-5904-0635)
- Gina M. Peloso (ORCID: https://orcid.org/0000-0002-5355-8636)
- Daniel H. Katz (ORCID: https://orcid.org/0000-0001-7237-8502)
- Jerome I. Rotter (ORCID: https://orcid.org/0000-0001-7191-1723)
- Peter Libby (ORCID: https://orcid.org/0000-0002-1502-502X)
- Sara Haidermota (ORCID: https://orcid.org/0000-0002-8588-3388)
- Jacqueline S. Dron (ORCID: https://orcid.org/0000-0002-3045-6530)
- Josef Coresh (ORCID: https://orcid.org/0000-0002-4598-0669)
- Wendy S. Post (ORCID: https://orcid.org/0000-0002-8655-5204)
- Pradeep Natarajan (ORCID: https://orcid.org/0000-0001-8402-7435)
- Thiago Rentz (ORCID: https://orcid.org/0000-0001-6908-8758)
- JoAnn E. Manson (ORCID: https://orcid.org/0000-0002-9426-7595)
- Robert E. Gerszten (ORCID: https://orcid.org/0000-0002-6767-7687)
- Christopher J. Gibson (ORCID: https://orcid.org/0000-0002-3700-5310)
- Christie Mitchell Ballantyne (ORCID: https://orcid.org/0000-0002-6432-1730)
- Thomas R. Austin
- Amy E. Lin (ORCID: https://orcid.org/0000-0002-0554-2832)
- Joshua S. Weinstock (ORCID: https://orcid.org/0000-0001-7013-1899)
- Joshua C. Bis (ORCID: https://orcid.org/0000-0002-3409-1110)
- Bing Yu (ORCID: https://orcid.org/0000-0003-4818-1077)
- Tetsushi Nakao (ORCID: https://orcid.org/0000-0001-9979-2682)
- Benjamin L. Ebert (ORCID: https://orcid.org/0000-0003-0197-5451)
- Stephen S. Rich (ORCID: https://orcid.org/0000-0003-3872-7793)
- Peter Ganz (ORCID: https://orcid.org/0000-0002-0437-8882)
- Siddhartha Jaiswal (ORCID: https://orcid.org/0000-0002-9597-0477)
- Alex P. Reiner (ORCID: https://orcid.org/0000-0002-1427-4470)
- James Wilson (ORCID: https://orcid.org/0000-0002-0911-8510)
- Yuan‐I Min (ORCID: https://orcid.org/0000-0003-2470-0004)
- Ngoc Quynh Nguyen
- Whitney Hornsby (ORCID: https://orcid.org/0000-0002-0672-0338)
- Shriienidhie Ganesh (ORCID: https://orcid.org/0000-0002-4226-7526)
- Gabriel K. Griffin (ORCID: https://orcid.org/0000-0002-4042-6757)
- T Antoine
- Leslie A. Lange
- Linke Li (ORCID: https://orcid.org/0009-0002-6350-5121)
Institutions
- Broad Institute (US)
- Boston University (US)
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- San Francisco General Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- Johns Hopkins University (US)
- Emory University (US)
- The University of Texas at San Antonio Health Science Center (US)
- University of California, San Francisco (US)
- Baylor College of Medicine (US)
- University of Washington (US)
- Johns Hopkins Medicine (US)
- Science for Life Laboratory (SE)
- UCLA Medical Center (US)
- Jackson Memorial Hospital (US)
- University of Mississippi Medical Center (US)
- Massachusetts General Hospital (US)
- Klinik Hietzing (AT)
- Fred Hutch Cancer Center (US)
- Dana-Farber Cancer Institute (US)
- Center for Systems Biology (US)
- Harvard Stem Cell Institute (US)
- University of Virginia (US)
- University of Colorado Anschutz Medical Campus (US)
- New York University (US)
- University of Gothenburg (SE)
- Vanderbilt University Medical Center (US)
- The University of Texas Health Science Center at Houston (US)
- Stanford University (US)
- KU Leuven (BE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-27
- DOI
- https://doi.org/10.1038/s41467-025-66755-z
- Citations
- 1
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 1.77
Funders
- Broad Institute
- National Heart, Lung, and Blood Institute
- National Human Genome Research Institute