Human Plasma Proteomic Profile of Clonal Hematopoiesis

Abstract Plasma proteomic profiles associated with subclinical somatic mutations in blood cells may offer novel insights in downstream clinical consequences. Here, we explore such patterns in clonal hematopoiesis of indeterminate potential (CHIP), which links to several cancer and non-cancer outcomes, including coronary artery disease. Among 12,911 ancestrally diverse participants (682 with CHIP) from NHLBI TOPMed with blood-based DNA sequencing and 1,148 common proteins measured by SomaScan, we identified 32 unique proteins associated with the most prevalent driver genes ( DNMT3A , TET2 , and ASXL1 ) after multiple testing corrections. These associations showed substantial heterogeneity by driver genes, sex, and race, were enriched for immune response and inflammation pathways, and were moderately replicated in UK Biobank (N=48,922) that used Olink for proteomics measurement. Murine single-cell RNA-sequencing data from aortic arch cells, inclusive of resident hematologic cells, in mice with Tet2 -/- bone marrow and wild-type mice revealed corroborating differential expression of TET2 -associated protein-encoding genes. Lastly, we apply these observations to identify 68 plasma proteins shared between CHIP and coronary artery disease.