High burden of clonal hematopoiesis in first responders exposed to the World Trade Center disaster

Sakshi Jasra; Orsolya Giricz; Rachel Zeig-Owens; Kith Pradhan; David G. Goldfarb; Angelica Barreto-Galvez; Alexander J. Silver; Jiahao Chen; Srabani Sahu; Shanisha Gordon-Mitchell; Gaurav S. Choudhary; Srinivas Aluri; Tushar D. Bhagat; Aditi Shastri; Cosmin A. Bejan; Shannon S. Stockton; Travis P. Spaulding; Victor Thiruthuvanathan; Hiroki Goto; Jeannine Gerhardt; Syed Hissam Haider; Arul Veerappan; Matthias Bartenstein; George Nwankwo; Ola Landgren; Michael D. Weiden; Jacqueline Lekostaj; Ryan Bender; Frederick Fletcher; Lee Greenberger; Benjamin L. Ebert; Ulrich Steidl; Britta Will; Anna Nolan; Advaitha Madireddy; Michael R. Savona; David J. Prezant; Amit Verma

doi:10.1038/s41591-022-01708-3

High burden of clonal hematopoiesis in first responders exposed to the World Trade Center disaster

Sakshi Jasra, Orsolya Giricz, Rachel Zeig-Owens, Kith Pradhan, David G. Goldfarb, Angelica Barreto-Galvez, Alexander J. Silver, Jiahao Chen, Srabani Sahu, Shanisha Gordon-Mitchell, Gaurav S. Choudhary, Srinivas Aluri, Tushar D. Bhagat, Aditi Shastri, Cosmin A. Bejan, Shannon S. Stockton, Travis P. Spaulding, Victor Thiruthuvanathan, Hiroki Goto, Jeannine GerhardtSyed Hissam Haider, Arul Veerappan, Matthias Bartenstein, George Nwankwo, Ola Landgren, Michael D. Weiden, Jacqueline Lekostaj, Ryan Bender, Frederick Fletcher, Lee Greenberger, Benjamin L. Ebert, Ulrich Steidl, Britta Will, Anna Nolan, Advaitha Madireddy, Michael R. Savona, David J. Prezant, Amit Verma

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	468-471
Number of pages	4
Journal	Nature Medicine
Volume	28
Issue number	3
DOIs	https://doi.org/10.1038/s41591-022-01708-3
State	Published - Mar 2022

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41591-022-01708-3

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Jasra, S., Giricz, O., Zeig-Owens, R., Pradhan, K., Goldfarb, D. G., Barreto-Galvez, A., Silver, A. J., Chen, J., Sahu, S., Gordon-Mitchell, S., Choudhary, G. S., Aluri, S., Bhagat, T. D., Shastri, A., Bejan, C. A., Stockton, S. S., Spaulding, T. P., Thiruthuvanathan, V., Goto, H., ... Verma, A. (2022). High burden of clonal hematopoiesis in first responders exposed to the World Trade Center disaster. Nature Medicine, 28(3), 468-471. https://doi.org/10.1038/s41591-022-01708-3

Jasra, S, Giricz, O, Zeig-Owens, R , Pradhan, K, Goldfarb, DG, Barreto-Galvez, A, Silver, AJ, Chen, J, Sahu, S, Gordon-Mitchell, S, Choudhary, GS, Aluri, S, Bhagat, TD, Shastri, A, Bejan, CA, Stockton, SS, Spaulding, TP, Thiruthuvanathan, V, Goto, H, Gerhardt, J, Haider, SH, Veerappan, A, Bartenstein, M, Nwankwo, G, Landgren, O, Weiden, MD, Lekostaj, J, Bender, R, Fletcher, F, Greenberger, L, Ebert, BL, Steidl, U , Will, B, Nolan, A, Madireddy, A, Savona, MR, Prezant, DJ & Verma, A 2022, 'High burden of clonal hematopoiesis in first responders exposed to the World Trade Center disaster', Nature Medicine, vol. 28, no. 3, pp. 468-471. https://doi.org/10.1038/s41591-022-01708-3

@article{490e96628fd14815b96305de933c4591,

title = "High burden of clonal hematopoiesis in first responders exposed to the World Trade Center disaster",

abstract = "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.",

author = "Sakshi Jasra and Orsolya Giricz and Rachel Zeig-Owens and Kith Pradhan and Goldfarb, {David G.} and Angelica Barreto-Galvez and Silver, {Alexander J.} and Jiahao Chen and Srabani Sahu and Shanisha Gordon-Mitchell and Choudhary, {Gaurav S.} and Srinivas Aluri and Bhagat, {Tushar D.} and Aditi Shastri and Bejan, {Cosmin A.} and Stockton, {Shannon S.} and Spaulding, {Travis P.} and Victor Thiruthuvanathan and Hiroki Goto and Jeannine Gerhardt and Haider, {Syed Hissam} and Arul Veerappan and Matthias Bartenstein and George Nwankwo and Ola Landgren and Weiden, {Michael D.} and Jacqueline Lekostaj and Ryan Bender and Frederick Fletcher and Lee Greenberger and Ebert, {Benjamin L.} and Ulrich Steidl and Britta Will and Anna Nolan and Advaitha Madireddy and Savona, {Michael R.} and Prezant, {David J.} and Amit Verma",

note = "Funding Information: A.V. has received research funding from Prelude, BMS, GSK, Incyte, Medpacto, Curis and Eli Lilly, is a scientific advisor for Stelexis, Novartis, Acceleron and Celgene, receives honoraria from Stelexis and Janssen and holds equity in Stelexis and Throws Exception. B.L.E. has received research funding from Celgene, Deerfield, Novartis and Calico and consulting fees from GRAIL. He is a member of the scientific advisory board and shareholder for Neomorph Therapeutics, TenSixteen Bio, Skyhawk Therapeutics and Exo Therapeutics. M.R.S has acted as a scientific advisor for Abbvie, BMS, CTI, Geron, Karyopharm, Novartis, Ryvu, Sierra Oncology, Taiho, Takeda, TG Therapeutics; has received research funding from ALX Oncology, Astex, Incyte, Takeda, TG Therapeutics; and has equity positions in Karyopharm, Ryvu. Funding Information: The work was supported by National Institutes of Health grants U01OH011933 (A.V.), U01OH012271 (A.V., R.Z.-O.), U01OH11300 (A.N.), F30DK127699 (A.J.S.), R01HL119326 (A.N.), R00HL136870 (A.M.) and T32GM007347 (A.J.S), NIOSH contracts 200-2011-39383, 200-2011-39378 and 200-2017-93326 (R.Z.-O.), the Jane and Myles Dempsey Fund (A.V.), Leukemia Lymphoma Society (A.V., M.R.S), the Evans MDS Foundation (A.V., M.R.S.), the Valvano Foundation (A.V.), the Adventure Alle Fund (M.R.S.), the Biff Ruttenberg Foundation (M.R.S.), the Beverly and George Rawlings Directorship (M.R.S.), the Ann Melly Scholarship (AJS) and a gift from the Leinbach family (A.V.). The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center{\textquoteright}s BioVU which is supported by numerous sources: institutional funding, private agencies and federal grants. These include the NIH funded Shared Instrumentation Grant S10RR025141, S10OD025092 and S10OD017985; and CTSA grants UL1TR002243, UL1TR000445 and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, R01HD074711; and additional funding sources listed at https://victr.vumc.org/biovu-funding/ . Funding Information: The work was supported by National Institutes of Health grants U01OH011933 (A.V.), U01OH012271 (A.V., R.Z.-O.), U01OH11300 (A.N.), F30DK127699 (A.J.S.), R01HL119326 (A.N.), R00HL136870 (A.M.) and T32GM007347 (A.J.S), NIOSH contracts 200-2011-39383, 200-2011-39378 and 200-2017-93326 (R.Z.-O.), the Jane and Myles Dempsey Fund (A.V.), Leukemia Lymphoma Society (A.V., M.R.S), the Evans MDS Foundation (A.V., M.R.S.), the Valvano Foundation (A.V.), the Adventure Alle Fund (M.R.S.), the Biff Ruttenberg Foundation (M.R.S.), the Beverly and George Rawlings Directorship (M.R.S.), the Ann Melly Scholarship (AJS) and a gift from the Leinbach family (A.V.). The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center?s BioVU which is supported by numerous sources: institutional funding, private agencies and federal grants. These include the NIH funded Shared Instrumentation Grant S10RR025141, S10OD025092 and S10OD017985; and CTSA grants UL1TR002243, UL1TR000445 and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, R01HD074711; and additional funding sources listed at https://victr.vumc.org/biovu-funding/. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2022",

month = mar,

doi = "10.1038/s41591-022-01708-3",

language = "English (US)",

volume = "28",

pages = "468--471",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

number = "3",

}

TY - JOUR

T1 - High burden of clonal hematopoiesis in first responders exposed to the World Trade Center disaster

AU - Jasra, Sakshi

AU - Giricz, Orsolya

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 - Funding Information: A.V. has received research funding from Prelude, BMS, GSK, Incyte, Medpacto, Curis and Eli Lilly, is a scientific advisor for Stelexis, Novartis, Acceleron and Celgene, receives honoraria from Stelexis and Janssen and holds equity in Stelexis and Throws Exception. B.L.E. has received research funding from Celgene, Deerfield, Novartis and Calico and consulting fees from GRAIL. He is a member of the scientific advisory board and shareholder for Neomorph Therapeutics, TenSixteen Bio, Skyhawk Therapeutics and Exo Therapeutics. M.R.S has acted as a scientific advisor for Abbvie, BMS, CTI, Geron, Karyopharm, Novartis, Ryvu, Sierra Oncology, Taiho, Takeda, TG Therapeutics; has received research funding from ALX Oncology, Astex, Incyte, Takeda, TG Therapeutics; and has equity positions in Karyopharm, Ryvu. Funding Information: The work was supported by National Institutes of Health grants U01OH011933 (A.V.), U01OH012271 (A.V., R.Z.-O.), U01OH11300 (A.N.), F30DK127699 (A.J.S.), R01HL119326 (A.N.), R00HL136870 (A.M.) and T32GM007347 (A.J.S), NIOSH contracts 200-2011-39383, 200-2011-39378 and 200-2017-93326 (R.Z.-O.), the Jane and Myles Dempsey Fund (A.V.), Leukemia Lymphoma Society (A.V., M.R.S), the Evans MDS Foundation (A.V., M.R.S.), the Valvano Foundation (A.V.), the Adventure Alle Fund (M.R.S.), the Biff Ruttenberg Foundation (M.R.S.), the Beverly and George Rawlings Directorship (M.R.S.), the Ann Melly Scholarship (AJS) and a gift from the Leinbach family (A.V.). The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center’s BioVU which is supported by numerous sources: institutional funding, private agencies and federal grants. These include the NIH funded Shared Instrumentation Grant S10RR025141, S10OD025092 and S10OD017985; and CTSA grants UL1TR002243, UL1TR000445 and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, R01HD074711; and additional funding sources listed at https://victr.vumc.org/biovu-funding/ . Funding Information: The work was supported by National Institutes of Health grants U01OH011933 (A.V.), U01OH012271 (A.V., R.Z.-O.), U01OH11300 (A.N.), F30DK127699 (A.J.S.), R01HL119326 (A.N.), R00HL136870 (A.M.) and T32GM007347 (A.J.S), NIOSH contracts 200-2011-39383, 200-2011-39378 and 200-2017-93326 (R.Z.-O.), the Jane and Myles Dempsey Fund (A.V.), Leukemia Lymphoma Society (A.V., M.R.S), the Evans MDS Foundation (A.V., M.R.S.), the Valvano Foundation (A.V.), the Adventure Alle Fund (M.R.S.), the Biff Ruttenberg Foundation (M.R.S.), the Beverly and George Rawlings Directorship (M.R.S.), the Ann Melly Scholarship (AJS) and a gift from the Leinbach family (A.V.). The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center?s BioVU which is supported by numerous sources: institutional funding, private agencies and federal grants. These include the NIH funded Shared Instrumentation Grant S10RR025141, S10OD025092 and S10OD017985; and CTSA grants UL1TR002243, UL1TR000445 and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, R01HD074711; and additional funding sources listed at https://victr.vumc.org/biovu-funding/. 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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UR - http://www.scopus.com/inward/citedby.url?scp=85125724413&partnerID=8YFLogxK

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 -

High burden of clonal hematopoiesis in first responders exposed to the World Trade Center disaster

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