Distinct characteristics of lymphoid and myeloid clonal hematopoiesis in World Trade Center first responders

Clonal hematopoiesis of indeterminate potential (CHIP) represents the presence of clonal somatic mutations in blood cells in otherwise healthy individuals. While CHIP is known to increase risk for hematologic malignancies and cardiovascular disease, its association with airborne carcinogens remains largely unknown. We investigated CHIP mutations in 9/11 World Trade Center (WTC) disaster responders (n=350), who experienced substantial exposure to a complex mix of airborne carcinogens. Ultra-deep whole-exome sequencing at 250X was performed on banked blood samples. We characterized CHIP mutations and their associations with clinical factors (age, ancestry, gender, body mass index, cardiovascular disease, stroke), laboratory parameters (peripheral blood counts), mental and cognitive assessments, exposure data, and HLA zygosity. Statistical methods included Fisher's exact test, Wilcoxon rank sum test, and multivariate logistic regression. Findings were compared to unexposed controls (n=293) analyzed using identical methods. Among WTC participants, CHIP prevalence was 34.2%, with myeloid-CHIP (M-CHIP) at 16.2% and lymphoid-CHIP (L-CHIP) at 21.4%. M-CHIP prevalence correlated positively with age (p=0.02), smoking history (p=0.01), and lower platelet counts (p=0.03). The most frequent M-CHIP mutations were in DNMT3A, TET2, PPM1D, while L-CHIP mutations were in EEF1A1, DDX11 and KMT2D. Notably, DDX11 mutations were associated with lower Montreal Cognitive Assessment scores (p=6.57e-03). Comparison with unexposed controls demonstrated higher CHIP prevalence in WTC responders, particularly in those 55 or younger. Study highlights the potential utility of deep sequencing for CHIP detection with clinical, laboratory and exposure data to develop personalized risk-adapted screening programs for cancer and other CHIP-related conditions in individuals exposed to airborne carcinogens.