Clonal Hematopoiesis Is Not Significantly Associated with Covid-19 Disease Severity

Yifan Zhou; Ruba N Shalhoub; Stephanie N Rogers; Shiqin Yu; Muxin Gu; Margarete Alice Fabre; Pedro M Quiros; Arch Diangson; Wenhan Deng; Shubha Anand; Wanhua Lu; Matthew Cullen; Anna L Godfrey; Jacobus Preller; Jérôme Hadjadj; Emmanuelle Jouanguy; Aurélie Cobat; Laurent Abel; Frédéric Rieux-Laucat; Benjamin Terrier; Alain Fischer; Laura Novik; Ingelise J Gordon; Larisa Strom; Martin Gaudinski; Andrea Lisco; Irini Sereti; Thomas J Gniadek; Andrea Biondi; Paolo Bonfanti; Luisa Imberti; Yu Zhang; Clifton L Dalgard; Kerry Dobbs; Helen C Su; Luigi D Notarangelo; Colin O Wu; Peter J M Openshaw; Malcolm Gracie Semple; Ziad Mallat; Kenneth Baillie; Cynthia E Dunbar; George S Vassiliou

doi:10.1182/blood.2022015721

Clonal Hematopoiesis Is Not Significantly Associated with Covid-19 Disease Severity

Yifan Zhou, Ruba N Shalhoub, Stephanie N Rogers, Shiqin Yu, Muxin Gu, Margarete Alice Fabre, Pedro M Quiros, Arch Diangson, Wenhan Deng, Shubha Anand, Wanhua Lu, Matthew Cullen, Anna L Godfrey, Jacobus Preller, Jérôme Hadjadj, Emmanuelle Jouanguy, Aurélie Cobat, Laurent Abel, Frédéric Rieux-Laucat, Benjamin TerrierAlain Fischer, Laura Novik, Ingelise J Gordon, Larisa Strom, Martin Gaudinski, Andrea Lisco, Irini Sereti, Thomas J Gniadek, Andrea Biondi, Paolo Bonfanti, Luisa Imberti, Yu Zhang, Clifton L Dalgard, Kerry Dobbs, Helen C Su, Luigi D Notarangelo, Colin O Wu, Peter J M Openshaw, Malcolm Gracie Semple, Ziad Mallat, Kenneth Baillie, Cynthia E Dunbar, George S Vassiliou

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

Abstract / Description of output

Clonal hematopoiesis (CH) describes the disproportionate expansion of a hematopoietic stem
cell (HSC) and its progeny, in association with leukemia-associated somatic mutations, most
commonly affecting the genes for epigenetic regulators DNMT3A, TET2 and ASXL1.
The prevalence and size of such clones rise with age, in association with changes in the driver gene landscape.10 CH is associated with an increased risk of hematologic malignancies, but also of cardiovascular disease (CVD), independently of other known CVD risk factors.11,12 The basis for
this increased CVD risk has been linked to hyperinflammatory positive feedback loops driven by increased cytokine release from clonal myeloid cells, particularly interleukin IL-6 and IL-1β.

Original language	English
Pages (from-to)	1650-1655
Journal	Blood
Volume	140
Issue number	14
Early online date	15 Jul 2022
DOIs	https://doi.org/10.1182/blood.2022015721
Publication status	Published - 6 Oct 2022

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10.1182/blood.2022015721

blood.2022015721Final published version, 599 KBLicence: Creative Commons: Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND)

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Zhou, Y., Shalhoub, R. N., Rogers, S. N., Yu, S., Gu, M., Fabre, M. A., Quiros, P. M., Diangson, A., Deng, W., Anand, S., Lu, W., Cullen, M., Godfrey, A. L., Preller, J., Hadjadj, J., Jouanguy, E., Cobat, A., Abel, L., Rieux-Laucat, F., ... Vassiliou, G. S. (2022). Clonal Hematopoiesis Is Not Significantly Associated with Covid-19 Disease Severity. Blood, 140(14), 1650-1655. https://doi.org/10.1182/blood.2022015721

@article{d47d55677fb44573b4dc424bbbb4da7b,

title = "Clonal Hematopoiesis Is Not Significantly Associated with Covid-19 Disease Severity",

abstract = "Clonal hematopoiesis (CH) describes the disproportionate expansion of a hematopoietic stemcell (HSC) and its progeny, in association with leukemia-associated somatic mutations, mostcommonly affecting the genes for epigenetic regulators DNMT3A, TET2 and ASXL1.The prevalence and size of such clones rise with age, in association with changes in the driver gene landscape.10 CH is associated with an increased risk of hematologic malignancies, but also of cardiovascular disease (CVD), independently of other known CVD risk factors.11,12 The basis forthis increased CVD risk has been linked to hyperinflammatory positive feedback loops driven by increased cytokine release from clonal myeloid cells, particularly interleukin IL-6 and IL-1β.",

author = "Yifan Zhou and Shalhoub, {Ruba N} and Rogers, {Stephanie N} and Shiqin Yu and Muxin Gu and Fabre, {Margarete Alice} and Quiros, {Pedro M} and Arch Diangson and Wenhan Deng and Shubha Anand and Wanhua Lu and Matthew Cullen and Godfrey, {Anna L} and Jacobus Preller and J{\'e}r{\^o}me Hadjadj and Emmanuelle Jouanguy and Aur{\'e}lie Cobat and Laurent Abel and Fr{\'e}d{\'e}ric Rieux-Laucat and Benjamin Terrier and Alain Fischer and Laura Novik and Gordon, {Ingelise J} and Larisa Strom and Martin Gaudinski and Andrea Lisco and Irini Sereti and Gniadek, {Thomas J} and Andrea Biondi and Paolo Bonfanti and Luisa Imberti and Yu Zhang and Dalgard, {Clifton L} and Kerry Dobbs and Su, {Helen C} and Notarangelo, {Luigi D} and Wu, {Colin O} and Openshaw, {Peter J M} and Semple, {Malcolm Gracie} and Ziad Mallat and Kenneth Baillie and Dunbar, {Cynthia E} and Vassiliou, {George S}",

note = "Funding Information: This research was funded in whole, or in part, by the Wellcome Trust 203151/Z/16/Z] and the UKRI Medical Research Council [MC_PC_17230]. For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. This work was supported by a European Hematology Association COVID-19 in Hematology Research Grant 2020 and a National Institutes of Health Intramural Targeted Anti-COVID-19 (ITAC) Award. G.S.V. is funded by a Cancer Research UK Senior Cancer Research Fellowship (C22324/A23015). The work was also supported in part by the Intramural Research Program of the National Heart, Lung, and Blood Institure and National Institute of Allergy and Infectious Diseases . Funding Information: Conflict-of-interest disclosure: G.S.V. is a consultant with STRM.BIO and receives a research grant from AstraZeneca. During 2021, T.J.G. was a paid consultant for Frenwal/Fresenius Kabi and became a full-time employee of the company in March 2022. The remaining authors declare no competing financial interests. Funding Information: This work used the computational resources of the National Institutes of Health (NIH) High Performance Computing Biowulf cluster and Wellcome-MRC Cambridge Stem Cell Institute High Performance Computing cluster. The NorthShore University Health System COVID-19 Convalescent Plasma collection program was initially supported by grants to the NorthShore Foundation, including a donation from the Rice Foundation, and support from NorthShore University HealthSystem Research Institute. Subsequently, NorthShore received funding from the Department of Defense (W911QY2090012-D.S.). The ISARIC4C is supported by grants from the NIHR (award CO-CIN-01), MRC (grant MC_PC_19059), NIHR Imperial Biomedical Research Centre (grant P45058), HPRU in Respiratory Infections at Imperial College London, and NIHR HPRU in Emerging and Zoonotic Infections at the University of Liverpool, in partnership with Public Health England (NIHR award 200907), Wellcome Trust, Department for International Development (215091/Z/18/Z), Bill & Melinda Gates Foundation (OPP1209135), Liverpool Experimental Cancer Medicine Centre (grant C18616/A25153), NIHR Biomedical Research Centre at Imperial College London (IS-BRC-1215–20013), and EU Platform for European Preparedness Against (Re-) Emerging Epidemics (PREPARE, FP7 project 602525). Funding Information: The authors are grateful to all physicians, nurses, and health care workers treating COVID-19 patients under very challenging circumstances and still being able to help with providing data for this paper. The authors are also very grateful to the 2648 frontline National Health Service clinical and research staff and volunteer medical students who collected these data in challenging circumstances. The authors thank the generosity of the participants and their families for their individual contributions in these difficult times. The authors acknowledge Lucy Lorris for extracting clinical information for ISARIC4C patients; Tovah Klein for providing samples and clinical information for NorthShore Hospital patients; Mary Magliocco, Michael Stack, Elana Shaw, Jason Barnett, Smilee Samuel, and Sandhya Xirasagar for maintaining LabKey database for NIAID Immune Response to COVID patients; Charla Andrews, Britta Flach, Emily Coates, Obrimpong Amoa-Awua, Maria Burgos Florez, Lasonji Holman, and Renunda Hicks for providing samples and clinical information for VRC 200 patients; and Elizabeth Laidlaw and Silvia Lage for providing samples and clinical information for CALYPSO patients. The authors thank Xiaolin Wu, Arati Raziuddin at the National Cancer Institute (NCI) Frederick Sequencing Facility, Yuesheng Li, Yan Luo, and Patrick Burr at the National Heart, Lung and Blood Institute (NHLBI) DNA Sequencing and Genomics Core for preparing sequencing library and sequencing. The authors are grateful for the assistance provided by Helen Matthews, Sarah Weber, James Chappell, and Wilna Oosthuyzen and thank Shu Huang at Cavendish Laboratory, University of Cambridge, for discussion on data processing. The authors also acknowledge the support of Jeremy J. Farrar and Nohoko Shindo. This work used the computational resources of the National Institutes of Health (NIH) High Performance Computing Biowulf cluster and Wellcome-MRC Cambridge Stem Cell Institute High Performance Computing cluster. The NorthShore University Health System COVID-19 Convalescent Plasma collection program was initially supported by grants to the NorthShore Foundation, including a donation from the Rice Foundation, and support from NorthShore University HealthSystem Research Institute. Subsequently, NorthShore received funding from the Department of Defense (W911QY2090012-D.S.). The ISARIC4C is supported by grants from the NIHR (award CO-CIN-01), MRC (grant MC_PC_19059), NIHR Imperial Biomedical Research Centre (grant P45058), HPRU in Respiratory Infections at Imperial College London, and NIHR HPRU in Emerging and Zoonotic Infections at the University of Liverpool, in partnership with Public Health England (NIHR award 200907), Wellcome Trust, Department for International Development (215091/Z/18/Z), Bill & Melinda Gates Foundation (OPP1209135), Liverpool Experimental Cancer Medicine Centre (grant C18616/A25153), NIHR Biomedical Research Centre at Imperial College London (IS-BRC-1215–20013), and EU Platform for European Preparedness Against (Re-) Emerging Epidemics (PREPARE, FP7 project 602525). This research was funded in whole, or in part, by the Wellcome Trust 203151/Z/16/Z] and the UKRI Medical Research Council [MC_PC_17230]. For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. This work was supported by a European Hematology Association COVID-19 in Hematology Research Grant 2020 and a National Institutes of Health Intramural Targeted Anti-COVID-19 (ITAC) Award. G.S.V. is funded by a Cancer Research UK Senior Cancer Research Fellowship (C22324/A23015). The work was also supported in part by the Intramural Research Program of the National Heart, Lung, and Blood Institure and National Institute of Allergy and Infectious Diseases. Contribution: G.S.V. C.E.D. and Z.M. conceived the study; G.S.V. C.E.D. J.K.B. Z.M. and Y.Z. designed and supervised the study; Y.Z. R.S. C.O.W. M.G. M.A.F. and P.M.Q. performed and advised on the bioinformatic and statistical analysis; S.N.R. S.Y. T.-H.S. A.D. W.D. S.A. W.L. and M.C. prepared library and sequenced samples; A.L.G. J.P. J.H. E.J. A.C. L.A. F.R.-L. B.T. A.F. I.J.G. L.N. L.S. M.R.G. A.L. I.S. T.J.G. A.B. P.B. L.I. C.L.D. Y.Z. K.D. H.C.S. L.D.N. P.J.M.O. and M.G.S. provided samples and clinical information; P.J.M.O. M.G.S. and J.K.B. set up the ISARIC4C cohort; and G.S.V. C.E.D. and Y.Z. wrote the manuscript with input from all coauthors.",

year = "2022",

month = oct,

day = "6",

doi = "10.1182/blood.2022015721",

language = "English",

volume = "140",

pages = "1650--1655",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "14",

}

Zhou, Y, Shalhoub, RN, Rogers, SN, Yu, S, Gu, M, Fabre, MA, Quiros, PM, Diangson, A, Deng, W, Anand, S, Lu, W, Cullen, M, Godfrey, AL, Preller, J, Hadjadj, J, Jouanguy, E, Cobat, A, Abel, L, Rieux-Laucat, F, Terrier, B, Fischer, A, Novik, L, Gordon, IJ, Strom, L, Gaudinski, M, Lisco, A, Sereti, I, Gniadek, TJ, Biondi, A, Bonfanti, P, Imberti, L, Zhang, Y, Dalgard, CL, Dobbs, K, Su, HC, Notarangelo, LD, Wu, CO, Openshaw, PJM, Semple, MG, Mallat, Z, Baillie, K, Dunbar, CE & Vassiliou, GS 2022, 'Clonal Hematopoiesis Is Not Significantly Associated with Covid-19 Disease Severity', Blood, vol. 140, no. 14, pp. 1650-1655. https://doi.org/10.1182/blood.2022015721

TY - JOUR

T1 - Clonal Hematopoiesis Is Not Significantly Associated with Covid-19 Disease Severity

AU - Zhou, Yifan

AU - Shalhoub, Ruba N

AU - Rogers, Stephanie N

AU - Yu, Shiqin

AU - Gu, Muxin

AU - Fabre, Margarete Alice

AU - Quiros, Pedro M

AU - Diangson, Arch

AU - Deng, Wenhan

AU - Anand, Shubha

AU - Lu, Wanhua

AU - Cullen, Matthew

AU - Godfrey, Anna L

AU - Preller, Jacobus

AU - Hadjadj, Jérôme

AU - Jouanguy, Emmanuelle

AU - Cobat, Aurélie

AU - Abel, Laurent

AU - Rieux-Laucat, Frédéric

AU - Terrier, Benjamin

AU - Fischer, Alain

AU - Novik, Laura

AU - Gordon, Ingelise J

AU - Strom, Larisa

AU - Gaudinski, Martin

AU - Lisco, Andrea

AU - Sereti, Irini

AU - Gniadek, Thomas J

AU - Biondi, Andrea

AU - Bonfanti, Paolo

AU - Imberti, Luisa

AU - Zhang, Yu

AU - Dalgard, Clifton L

AU - Dobbs, Kerry

AU - Su, Helen C

AU - Notarangelo, Luigi D

AU - Wu, Colin O

AU - Openshaw, Peter J M

AU - Semple, Malcolm Gracie

AU - Mallat, Ziad

AU - Baillie, Kenneth

AU - Dunbar, Cynthia E

AU - Vassiliou, George S

N1 - Funding Information: This research was funded in whole, or in part, by the Wellcome Trust 203151/Z/16/Z] and the UKRI Medical Research Council [MC_PC_17230]. For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. This work was supported by a European Hematology Association COVID-19 in Hematology Research Grant 2020 and a National Institutes of Health Intramural Targeted Anti-COVID-19 (ITAC) Award. G.S.V. is funded by a Cancer Research UK Senior Cancer Research Fellowship (C22324/A23015). The work was also supported in part by the Intramural Research Program of the National Heart, Lung, and Blood Institure and National Institute of Allergy and Infectious Diseases . Funding Information: Conflict-of-interest disclosure: G.S.V. is a consultant with STRM.BIO and receives a research grant from AstraZeneca. During 2021, T.J.G. was a paid consultant for Frenwal/Fresenius Kabi and became a full-time employee of the company in March 2022. The remaining authors declare no competing financial interests. Funding Information: This work used the computational resources of the National Institutes of Health (NIH) High Performance Computing Biowulf cluster and Wellcome-MRC Cambridge Stem Cell Institute High Performance Computing cluster. The NorthShore University Health System COVID-19 Convalescent Plasma collection program was initially supported by grants to the NorthShore Foundation, including a donation from the Rice Foundation, and support from NorthShore University HealthSystem Research Institute. Subsequently, NorthShore received funding from the Department of Defense (W911QY2090012-D.S.). The ISARIC4C is supported by grants from the NIHR (award CO-CIN-01), MRC (grant MC_PC_19059), NIHR Imperial Biomedical Research Centre (grant P45058), HPRU in Respiratory Infections at Imperial College London, and NIHR HPRU in Emerging and Zoonotic Infections at the University of Liverpool, in partnership with Public Health England (NIHR award 200907), Wellcome Trust, Department for International Development (215091/Z/18/Z), Bill & Melinda Gates Foundation (OPP1209135), Liverpool Experimental Cancer Medicine Centre (grant C18616/A25153), NIHR Biomedical Research Centre at Imperial College London (IS-BRC-1215–20013), and EU Platform for European Preparedness Against (Re-) Emerging Epidemics (PREPARE, FP7 project 602525). Funding Information: The authors are grateful to all physicians, nurses, and health care workers treating COVID-19 patients under very challenging circumstances and still being able to help with providing data for this paper. The authors are also very grateful to the 2648 frontline National Health Service clinical and research staff and volunteer medical students who collected these data in challenging circumstances. The authors thank the generosity of the participants and their families for their individual contributions in these difficult times. The authors acknowledge Lucy Lorris for extracting clinical information for ISARIC4C patients; Tovah Klein for providing samples and clinical information for NorthShore Hospital patients; Mary Magliocco, Michael Stack, Elana Shaw, Jason Barnett, Smilee Samuel, and Sandhya Xirasagar for maintaining LabKey database for NIAID Immune Response to COVID patients; Charla Andrews, Britta Flach, Emily Coates, Obrimpong Amoa-Awua, Maria Burgos Florez, Lasonji Holman, and Renunda Hicks for providing samples and clinical information for VRC 200 patients; and Elizabeth Laidlaw and Silvia Lage for providing samples and clinical information for CALYPSO patients. The authors thank Xiaolin Wu, Arati Raziuddin at the National Cancer Institute (NCI) Frederick Sequencing Facility, Yuesheng Li, Yan Luo, and Patrick Burr at the National Heart, Lung and Blood Institute (NHLBI) DNA Sequencing and Genomics Core for preparing sequencing library and sequencing. The authors are grateful for the assistance provided by Helen Matthews, Sarah Weber, James Chappell, and Wilna Oosthuyzen and thank Shu Huang at Cavendish Laboratory, University of Cambridge, for discussion on data processing. The authors also acknowledge the support of Jeremy J. Farrar and Nohoko Shindo. This work used the computational resources of the National Institutes of Health (NIH) High Performance Computing Biowulf cluster and Wellcome-MRC Cambridge Stem Cell Institute High Performance Computing cluster. The NorthShore University Health System COVID-19 Convalescent Plasma collection program was initially supported by grants to the NorthShore Foundation, including a donation from the Rice Foundation, and support from NorthShore University HealthSystem Research Institute. Subsequently, NorthShore received funding from the Department of Defense (W911QY2090012-D.S.). The ISARIC4C is supported by grants from the NIHR (award CO-CIN-01), MRC (grant MC_PC_19059), NIHR Imperial Biomedical Research Centre (grant P45058), HPRU in Respiratory Infections at Imperial College London, and NIHR HPRU in Emerging and Zoonotic Infections at the University of Liverpool, in partnership with Public Health England (NIHR award 200907), Wellcome Trust, Department for International Development (215091/Z/18/Z), Bill & Melinda Gates Foundation (OPP1209135), Liverpool Experimental Cancer Medicine Centre (grant C18616/A25153), NIHR Biomedical Research Centre at Imperial College London (IS-BRC-1215–20013), and EU Platform for European Preparedness Against (Re-) Emerging Epidemics (PREPARE, FP7 project 602525). This research was funded in whole, or in part, by the Wellcome Trust 203151/Z/16/Z] and the UKRI Medical Research Council [MC_PC_17230]. For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. This work was supported by a European Hematology Association COVID-19 in Hematology Research Grant 2020 and a National Institutes of Health Intramural Targeted Anti-COVID-19 (ITAC) Award. G.S.V. is funded by a Cancer Research UK Senior Cancer Research Fellowship (C22324/A23015). The work was also supported in part by the Intramural Research Program of the National Heart, Lung, and Blood Institure and National Institute of Allergy and Infectious Diseases. Contribution: G.S.V. C.E.D. and Z.M. conceived the study; G.S.V. C.E.D. J.K.B. Z.M. and Y.Z. designed and supervised the study; Y.Z. R.S. C.O.W. M.G. M.A.F. and P.M.Q. performed and advised on the bioinformatic and statistical analysis; S.N.R. S.Y. T.-H.S. A.D. W.D. S.A. W.L. and M.C. prepared library and sequenced samples; A.L.G. J.P. J.H. E.J. A.C. L.A. F.R.-L. B.T. A.F. I.J.G. L.N. L.S. M.R.G. A.L. I.S. T.J.G. A.B. P.B. L.I. C.L.D. Y.Z. K.D. H.C.S. L.D.N. P.J.M.O. and M.G.S. provided samples and clinical information; P.J.M.O. M.G.S. and J.K.B. set up the ISARIC4C cohort; and G.S.V. C.E.D. and Y.Z. wrote the manuscript with input from all coauthors.

PY - 2022/10/6

Y1 - 2022/10/6

N2 - Clonal hematopoiesis (CH) describes the disproportionate expansion of a hematopoietic stemcell (HSC) and its progeny, in association with leukemia-associated somatic mutations, mostcommonly affecting the genes for epigenetic regulators DNMT3A, TET2 and ASXL1.The prevalence and size of such clones rise with age, in association with changes in the driver gene landscape.10 CH is associated with an increased risk of hematologic malignancies, but also of cardiovascular disease (CVD), independently of other known CVD risk factors.11,12 The basis forthis increased CVD risk has been linked to hyperinflammatory positive feedback loops driven by increased cytokine release from clonal myeloid cells, particularly interleukin IL-6 and IL-1β.

AB - Clonal hematopoiesis (CH) describes the disproportionate expansion of a hematopoietic stemcell (HSC) and its progeny, in association with leukemia-associated somatic mutations, mostcommonly affecting the genes for epigenetic regulators DNMT3A, TET2 and ASXL1.The prevalence and size of such clones rise with age, in association with changes in the driver gene landscape.10 CH is associated with an increased risk of hematologic malignancies, but also of cardiovascular disease (CVD), independently of other known CVD risk factors.11,12 The basis forthis increased CVD risk has been linked to hyperinflammatory positive feedback loops driven by increased cytokine release from clonal myeloid cells, particularly interleukin IL-6 and IL-1β.

U2 - 10.1182/blood.2022015721

DO - 10.1182/blood.2022015721

M3 - Letter

C2 - 35839449

SN - 0006-4971

VL - 140

SP - 1650

EP - 1655

JO - Blood

JF - Blood

IS - 14

ER -

Clonal Hematopoiesis Is Not Significantly Associated with Covid-19 Disease Severity

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