TY - JOUR
T1 - High burden of clonal hematopoiesis in first responders exposed to the World Trade Center disaster
AU - Jasra, Sakshi
AU - Giricz, Orsi
AU - Zeig-Owens, Rachel
AU - Pradhan, Kith
AU - Goldfarb, David G.
AU - Barreto-Galvez, Angelica
AU - Silver, Alexander J.
AU - Chen, Jiahao
AU - Sahu, Srabani
AU - Gordon-Mitchell, Shanisha
AU - Choudhary, Gaurav S.
AU - Aluri, Srinivas
AU - Bhagat, Tushar D.
AU - Shastri, Aditi
AU - Bejan, Cosmin A.
AU - Stockton, Shannon S.
AU - Spaulding, Travis P.
AU - Thiruthuvanathan, Victor
AU - Goto, Hiroki
AU - Gerhardt, Jeannine
AU - Haider, Syed Hissam
AU - Veerappan, Arul
AU - Bartenstein, Matthias
AU - Nwankwo, George
AU - Landgren, Ola
AU - Weiden, Michael D.
AU - Lekostaj, Jacqueline
AU - Bender, Ryan
AU - Fletcher, Frederick
AU - Greenberger, Lee
AU - Ebert, Benjamin L.
AU - Steidl, Ulrich
AU - Will, Britta
AU - Nolan, Anna
AU - Madireddy, Advaitha
AU - Savona, Michael R.
AU - Prezant, David J.
AU - Verma, Amit
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/3
Y1 - 2022/3
N2 - The terrorist attacks on the World Trade Center (WTC) created an unprecedented environmental exposure to aerosolized dust, gases and potential carcinogens. Clonal hematopoiesis (CH) is defined as the acquisition of somatic mutations in blood cells and is associated with smoking and exposure to genotoxic stimuli. Here we show that deep targeted sequencing of blood samples identified a significantly higher proportion of WTC-exposed first responders with CH (10%; 48 out of 481) when compared with non-WTC-exposed firefighters (6.7%; 17 out of 255; odds ratio, 3.14; 95% confidence interval, 1.64–6.03; P = 0.0006) after controlling for age, sex and race/ethnicity. The frequency of somatic mutations in WTC-exposed first responders showed an age-related increase and predominantly affected DNMT3A, TET2 and other CH-associated genes. Exposure of lymphoblastoid cells to WTC particulate matter led to dysregulation of DNA replication at common fragile sites in vitro. Moreover, mice treated with WTC particulate matter developed an increased burden of mutations in hematopoietic stem and progenitor cell compartments. In summary, the high burden of CH in WTC-exposed first responders provides a rationale for enhanced screening and preventative efforts in this population.
AB - The terrorist attacks on the World Trade Center (WTC) created an unprecedented environmental exposure to aerosolized dust, gases and potential carcinogens. Clonal hematopoiesis (CH) is defined as the acquisition of somatic mutations in blood cells and is associated with smoking and exposure to genotoxic stimuli. Here we show that deep targeted sequencing of blood samples identified a significantly higher proportion of WTC-exposed first responders with CH (10%; 48 out of 481) when compared with non-WTC-exposed firefighters (6.7%; 17 out of 255; odds ratio, 3.14; 95% confidence interval, 1.64–6.03; P = 0.0006) after controlling for age, sex and race/ethnicity. The frequency of somatic mutations in WTC-exposed first responders showed an age-related increase and predominantly affected DNMT3A, TET2 and other CH-associated genes. Exposure of lymphoblastoid cells to WTC particulate matter led to dysregulation of DNA replication at common fragile sites in vitro. Moreover, mice treated with WTC particulate matter developed an increased burden of mutations in hematopoietic stem and progenitor cell compartments. In summary, the high burden of CH in WTC-exposed first responders provides a rationale for enhanced screening and preventative efforts in this population.
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U2 - 10.1038/s41591-022-01708-3
DO - 10.1038/s41591-022-01708-3
M3 - Article
C2 - 35256801
AN - SCOPUS:85125724413
SN - 1078-8956
VL - 28
SP - 468
EP - 471
JO - Nature Medicine
JF - Nature Medicine
IS - 3
ER -
