Human Plasma Proteomic Profile of Clonal Hematopoiesis

Zhi Yu; Amélie Vromman; Ngoc Quynh Nguyen; Art Schuermans; Linke Li; Thiago Rentz; Tetsushi Nakao; Shamsudheen Karuthedath Vellarikkal; Md Mesbah Uddin; Abhishek Niroula; Gabriel Kenneth Griffin; Michael C. Honigberg; Amy Erica Lin; Christopher James Gibson; Daniel H. Katz; Usman A. Tahir; Shi Fang; Jacqueline S. Dron; Michael Pan; Sara Haidermota; Shriienidhie Ganesh; Tajmara Antoine; Joshua S. Weinstock; Thomas R. Austin; Ramachandran Srini Vasan; Gina Marie Peloso; Whitney Hornsby; Peter Ganz; JoAnn E. Manson; Bernhard Haring

doi:10.1038/s41467-025-66755-z

GeneticsNature CommunicationsNov 27, 2025

Peer-reviewed journal article

Human Plasma Proteomic Profile of Clonal Hematopoiesis

Zhi Yu iD, Amélie Vromman iD, Ngoc Quynh Nguyen, Art Schuermans iD, Linke Li iD, Thiago Rentz iD, Tetsushi Nakao iD, Shamsudheen Karuthedath Vellarikkal iD, Md Mesbah Uddin iD, Abhishek Niroula iD, Gabriel Kenneth Griffin iD, Michael C. Honigberg iD, Amy Erica Lin iD, Christopher James Gibson iD, Daniel H. Katz iD, Usman A. Tahir iD, Shi Fang, Jacqueline S. Dron iD, Michael Pan iD, Sara Haidermota iD, Shriienidhie Ganesh iD, Tajmara Antoine, Joshua S. Weinstock iD, Thomas R. Austin iD, Ramachandran Srini Vasan iD, , Pradeep Natarajan iD

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Abstract

Plasma proteomic profiles associated with subclinical somatic mutations in blood cells may offer novel insights into downstream clinical consequences. Here, we explore such 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 ancestrally diverse participants (3,881 with CHIP) from NHLBI TOPMed and UK Biobank with blood-based DNA sequencing and proteomic measurements (1,148 proteins by SomaScan in TOPMed and 2,917 proteins by Olink in UK Biobank), we identified 32 and 345 unique proteins from TOPMed and UK Biobank, respectively, associated with the most prevalent driver genes (DNMT3A, TET2, and ASXL1). These associations showed 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, disentangled causal proteomic perturbations from TET2 CHIP. Lastly, we identified plasma proteins shared between CHIP and CAD.