Faculty, Staff and Student Publications

Language

English

Publication Date

11-27-2025

Journal

Nature Communications

DOI

10.1038/s41467-025-66755-z

PMID

41309676

PMCID

PMC12748892

PubMedCentral® Posted Date

11-27-2025

PubMedCentral® Full Text Version

Post-print

Abstract

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.

Keywords

Humans, Clonal Hematopoiesis, Dioxygenases, Animals, Proteomics, Mice, Female, DNA Methyltransferase 3A, DNA-Binding Proteins, Male, Proto-Oncogene Proteins, DNA (Cytosine-5-)-Methyltransferases, Coronary Artery Disease, Proteome, Repressor Proteins, Blood Proteins, Mice, Knockout, Middle Aged, Mutation, Aged, Mendelian Randomization Analysis, Molecular medicine, Population genetics, Epidemiology

Published Open-Access

yes

Download

Included in

Public Health Commons

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.