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Yu Z, Vromman A, Nguyen NQH, Schuermans A, Li L, Rentz T, Nakao T, Vellarikkal SK, Uddin MM, Niroula A, Griffin G, Honigberg MC, Lin AE, Gibson CJ, Katz DH, Tahir UA, Fang S, Dron JS, Pan M, Haidermota S, Ganesh S, Antoine T, Weinstock J, Austin TR, Vasan RS, Peloso GM, Hornsby W, Ganz P, Manson JE, Haring B, Kooperberg C, Reiner AP, Bis JC, Psaty BM, Min YI, Correa A, Lange LA, Post WS, Rotter JI, Rich SS, Wilson JG, Ebert BL, Yu B, Ballantyne CM, Coresh J, Sankaran VG, Bick AG, Jaiswal S, Gerszten RE, NHLBI Trans-Omics for Precision Medicine , Libby P, Gupta RM, Natarajan P
Nat Commun 16 (1) 11688 [2025-11-27; online 2025-11-27]
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.
PubMed 41309676
DOI 10.1038/s41467-025-66755-z
Crossref 10.1038/s41467-025-66755-z
pmc: PMC12748892
pii: 10.1038/s41467-025-66755-z