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

BACKGROUND Clonal hematopoiesis of indeterminate potential (CHIP) is a condition when healthy individuals harbor clonal mutations in myeloid (M-CHIP) and/or lymphoid (L-CHIP) cells at variant allele fraction (VAF) ≥0.02. While CHIP is associated with an increased risk of hematologic malignancy and cardiovascular disease, its association with airborne carcinogens is largely unknown. OBJECTIVES Here, we studied M/L-CHIP in responders to the 9/11 terrorist attacks on the World Trade Center (WTC), who were exposed to a complex mix of airborne carcinogens. Then we explored the association of CHIP mutations with phenotypes such as age, ancestry, exposure, HLA zygosity, and other clinical, laboratory, mental and cognitive data. Finally, we compared CHIP prevalence in WTC responders to 293 unexposed controls. METHODS Using banked peripheral blood and ultra-deep whole-exome sequencing at 250X, we characterized CHIP mutations and their interaction with clinical, mental and cognitive characteristics, exposure, peripheral blood counts, and HLA zygosity in 350 WTC responders. We used Fisher′s exact test for categorical variables; Wilcoxon rank sum test for continuous variables; and logistic regression for multivariate analysis. RESULTS Among WTC participants, M-CHIP prevalence was 16.2% and L-CHIP 21.4%. M-CHIP prevalence increased with age (p=0.02), was elevated in previous-smokers (p=0.01), and associated with lower platelet counts (p=0.03). The most frequently occurring genes for M-CHIP were DNMT3A, TET2, PPM1D and for L-CHIP were EEF1A1, DDX11 and KMT2D. Notably, harboring a DDX11 mutation associated with a lower Montreal Cognitive Assessment score (p=6.57e-03). Overall, M/L-CHIP was more prevalent in WTC responders versus controls. DISCUSSION Study results will inform the development of personalized risk-adapted CHIP and cancer screening programs in individuals exposed to airborne carcinogens.