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Cited by 733Acute Myeloid Leukemia ResearchGenetic Associations and EpidemiologyCancer Genomics and Diagnostics

Inherited causes of clonal haematopoiesis in 97,691 whole genomes

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Bick, Alexander G., Weinstock, Joshua S., Nandakumar, Satish K., Fulco, Charles P., Bao, Erik L., Zekavat, Seyedeh M., Szeto, Mindy D., Liao, Xiaotian +407 more·2020·Nature
DOI 10.1038/s41586-020-2819-2PMC PMC7944936
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Abstract

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown 1. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer 2-4 and coronary heart disease 5-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)6. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

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Crossref · 10.1038/s41586-020-2819-2

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  • Clone size, approximated by variant allele fraction, has previously been shown to be an important predictor of risk for blood cancer and cardiovascular outcomes.

    “Clone size, which is approximated by the variant allele fraction (VAF), has previously been shown to be an important predictor of risk for blood cancer1,17 and cardiovascular outcomes8,9.”

    From Clonal hematopoiesis is associated with protection from Alzheimer’s disease (2023) · cites this paper as [9]

    Extended Data Fig. 1 (page unavailable) explicitly uses variant allele fraction to measure CHIP clone size. The Abstract and ‘Germline genetic determinants of CHIP’ section (pages unavailable) describe associations between CHIP and hematologic cancer or cardiovascular disease, but do not establish that clone size predicts risk for either outcome. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Positive correlations are observed between IL-6 levels and DNMT3A, TET2, and ASXL1 mutant CH, and heightened IL-18 levels with JAK2 and SF3B1.

    “positive correlations were observed between IL-6 levels and DNMT3A, TET2, and ASXL1 mutant CH, heightened IL-18 levels with JAK2 and SF3B1 [20]”

    From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [20]

    The CHIP phenotypic associations section (page not specified) reports increased IL-6 for CHIP carriers in aggregate and increased IL-18 for JAK2 and SF3B1 CHIP. It does not report separate positive IL-6 associations for DNMT3A, TET2, and ASXL1 CHIP; its gene-specific finding for TET2 concerns IL-1β. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Increased levels of inflammatory cytokines and chemokines are significantly associated with CH in human studies, even following stem cell transplantation with donor-derived CH in the hosts.

    “Increased levels of inflammatory cytokines and chemokines have been recognized as a significant association with CH in human studies, even following stem cell transplantation with donor-derived CH in the hosts [20,32,58].”

    From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [20]

    The CHIP phenotypic associations section reports increased IL-6 in CHIP carriers and increased IL-1β or IL-18 for carriers with specific driver mutations, supporting the human cytokine association. The passages do not establish an association with chemokines or address donor-derived CH following stem cell transplantation. Page numbers were not available in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Elevated IL-8 and IL-1β levels are reported in patients with TET2 CH in the PROMIS study.

    “Elevated IL-8 and IL-1β levels have been reported in patients with TET2 CH in the Pakistan Risk of Myocardial Infarction Study (PROMIS) [20,32]”

    From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [20]

    The CHIP phenotypic associations section (page unavailable) reports increased IL-1β in people with TET2 CHIP. Our copy does not report increased IL-8 in that group or identify PROMIS as the setting for this finding (searched: IL-8 and PROMIS). (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • In several cohorts, the variant allele frequencies of clonal hematopoiesis clones are typically small and do not expand significantly without additional transforming events.

    “It has been observed in several cohorts that the VAFs of CH clones are typically small and do not expand significantly without additional transforming events [20,88].”

    From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [20]

    The paper reports a median CHIP variant allele fraction of 16% across its participants, which supports the description of typically modest clone sizes (Abstract; no page given). It does not report that clones remain stable over time or that significant expansion requires additional transforming events. Its finding that no tested germline variants were significantly associated with clonal expansion does not establish either point (Germline genetic determinants of CHIP; no page given). (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 1

  1. [10]Jaiswal S. Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes. New England Journal of Medicine 371, 2488– 2498 (2014). PMC4306669 25426837

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Bick, A. G., Weinstock, J. S., Nandakumar, S. K., Fulco, C. P., Bao, E. L., Zekavat, S. M., Szeto, M. D., Liao, X., Leventhal, M. J., Nasser, J., Chang, K., Laurie, C., Burugula, B. B., Gibson, C. J., Niroula, A., Lin, A. E., Taub, M. A., Aguet, F., Ardlie, K., Mitchell, B. D., Barnes, K. C., Moscati, A., Fornage, M., Redline, S., Psaty, B. M., Silverman, E. K., Weiss, S. T., Palmer, N. D., Vasan, R. S., Burchard, E. G., Kardia, S. L. R., He, J., Kaplan, R. C., Smith, N. L., Arnett, D. K., Schwartz, D. A., Correa, A., de Andrade, M., Guo, X., Konkle, B. A., Custer, B., Peralta, J. M., Gui, H., Meyers, D. A., McGarvey, S. T., Chen, I. Y.-D., Shoemaker, M. B., Peyser, P. A., Broome, J. G., Gogarten, S. M., Wang, F. F., Wong, Q., Montasser, M. E., Daya, M., Kenny, E. E., North, K. E., Launer, L. J., Cade, B. E., Bis, J. C., Cho, M. H., Lasky-Su, J., Bowden, D. W., Cupples, L. A., Mak, A. C. Y., Becker, L. C., Smith, J. A., Kelly, T. N., Aslibekyan, S., Heckbert, S. R., Tiwari, H. K., Yang, I. V., Heit, J. A., Lubitz, S. A., Johnsen, J. M., Curran, J. E., Wenzel, S. E., Weeks, D. E., Rao, D. C., Darbar, D., Moon, J.-Y., Tracy, R. P., Buth, E. J., Rafaels, N., Loos, R. J. F., Durda, P., Liu, Y., Hou, L., Lee, J., Kachroo, P., Freedman, B. I., Levy, D., Bielak, L. F., Hixson, J. E., Floyd, J. S., Whitsel, E. A., Ellinor, P. T., Irvin, M. R., Fingerlin, T. E., Raffield, L. M., Armasu, S. M., Wheeler, M. M., Sabino, E. C., Blangero, J., Williams, L. K., Levy, B. D., Sheu, W. H.-H., Roden, D. M., Boerwinkle, E., Manson, J. E., Mathias, R. A., Desai, P., Taylor, K. D., Johnson, A. D., NHLBI Trans-Omics for Precision Medicine Consortium, Abe, N., Albert, C., Almasy, L., Alonso, A., Ament, S., Anderson, P., Anugu, P., Applebaum-Bowden, D., Arking, D., Ashley-Koch, A., Aslibekyan, S., Assimes, T., Avramopoulos, D., Barnard, J., Barr, R. G., Barron-Casella, E., Barwick, L., Beaty, T., Beck, G., Becker, D., Beer, R., Beitelshees, A., Benjamin, E., Benos, P., Bezerra, M., Bielak, L., Bowler, R., Brody, J., Broeckel, U., Bunting, K., Bustamante, C., Cardwell, J., Carey, V., Carty, C., Casaburi, R., Casella, J., Castaldi, P., Chaffin, M., Chang, C., Chang, Y.-C., Chasman, D., Chavan, S., Chen, B.-J., Chen, W.-M., Choi, S. H., Chuang, L.-M., Chung, M., Chung, R.-H., Clish, C., Comhair, S., Cornell, E., Crandall, C., Crapo, J., Curtis, J., Damcott, C., Das, S., David, S., Davis, C., DeBaun, M., Deka, R., DeMeo, D., Devine, S., Duan, Q., Duggirala, R., Dutcher, S., Eaton, C., Ekunwe, L., Boueiz, A. E., Emery, L., Erzurum, S., Farber, C., Flickinger, M., Franceschini, N., Frazar, C., Fu, M., Fullerton, S. M., Fulton, L., Gabriel, S., Gan, W., Gao, S., Gao, Y., Gass, M., Gelb, B., Geng, X., Geraci, M., Germer, S., Gerszten, R., Ghosh, A., Gibbs, R., Gignoux, C., Gladwin, M., Glahn, D., Gong, D.-W., Goring, H., Graw, S., Grine, D., Gu, C. C., Guan, Y., Gupta, N., Haessler, J., Hall, M., Harris, D., Hawley, N. L., Heavner, B., Hernandez, R., Herrington, D., Hersh, C., Hidalgo, B., Hobbs, B., Hokanson, J., Hong, E., Hoth, K., Hsiung, C., Hung, Y.-J., Huston, H., Hwu, C. M., Jackson, R., Jain, D., Jaquish, C., Jhun, M. A., Johnson, C., Johnston, R., Jones, K., Kang, H. M., Kelly, S., Kessler, M., Khan, A., Kim, W., Kinney, G., Kramer, H., Lange, C., LeBoff, M., Lee, S. S., Lee, W.-J., LeFaive, J., Levine, D., Lewis, J., Li, X., Li, Y., Lin, H., Lin, H., Lin, K. H., Lin, X., Liu, S., Liu, Y., Lunetta, K., Luo, J., Mahaney, M., Make, B., Manichaikul, A., Margolin, L., Martin, L., Mathai, S., May, S., McArdle, P., McDonald, M.-L., McFarland, S., McGoldrick, D., McHugh, C., Mei, H., Mestroni, L., Mikulla, J., Min, N., Minear, M., Minster, R. L., Moll, M., Montgomery, C., Musani, S., Mwasongwe, S., Mychaleckyj, J. C., Nadkarni, G., Naik, R., Naseri, T., Nekhai, S., Nelson, S. C., Neltner, B., Nickerson, D., O’Connell, J., O’Connor, T., Ochs-Balcom, H., Paik, D., Pankow, J., Papanicolaou, G., Parsa, A., Perez, M., Perry, J., Peters, U., Peyser, P., Phillips, L. S., Pollin, T., Post, W., Becker, J. P., Boorgula, M. P., Preuss, M., Qasba, P., Qiao, D., Qin, Z., Rasmussen-Torvik, L., Ratan, A., Reed, R., Regan, E., Sefuiva Reupena, M., Rice, K., Roselli, C., Ruczinski, I., Russell, P., Ruuska, S., Ryan, K., Saleheen, D., Salimi, S., Salzberg, S., Sandow, K., Scheller, C., Schmidt, E., Schwander, K., Sciurba, F., Seidman, C., Seidman, J., Sheehan, V., Sherman, S. L., Shetty, A., Shetty, A., Silver, B., Smith, J., Smith, T., Smoller, S., Snively, B., Snyder, M., Sofer, T., Sotoodehnia, N., Stilp, A. M., Storm, G., Streeten, E., Su, J. L., Sung, Y. J., Sylvia, J., Szpiro, A., Sztalryd, C., Taliun, D., Tang, H., Taylor, M., Taylor, S., Telen, M., Thornton, T. A., Threlkeld, M., Tinker, L., Tirschwell, D., Tishkoff, S., Tiwari, H., Tong, C., Tsai, M., Vaidya, D., Berg, D. V. D., VandeHaar, P., Vrieze, S., Walker, T., Wallace, R., Walts, A., Wang, H., Watson, K., Weir, B., Weng, L.-C., Wessel, J., Willer, C., Williams, K., Wilson, C., Wu, J., Xu, H., Yanek, L., Yang, R., Zaghloul, N., Zhang, Y., Zhao, S. X., Zhao, W., Zhi, D., Zhou, X., Zhu, X., Zody, M., Zoellner, S., Auer, P. L., Kooperberg, C., Laurie, C. C., Blackwell, T. W., Smith, A. V., Zhao, H., Lange, E., Lange, L., Rich, S. S., Rotter, J. I., Wilson, J. G., Scheet, P., Kitzman, J. O., Lander, E. S., Engreitz, J. M., Ebert, B. L., Reiner, A. P., Jaiswal, S., Abecasis, G., Sankaran, V. G., Kathiresan, S., & Natarajan, P.
Affiliations
  • Broad Institute (US)
  • University of Michigan (US)
  • University of Colorado Anschutz (US)
  • The University of Texas MD Anderson Cancer Center (US)
  • University of Washington (US)
  • Dana-Farber Cancer Institute (US)
  • Brigham and Women's Hospital (US)
  • Johns Hopkins University (US)
  • University of Maryland, Baltimore (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (US)
  • Kaiser Permanente Washington Health Research Institute (US)
  • Wake Forest University Health Sciences (US)
  • Boston University (US)
  • University of California, San Francisco (US)
  • Tulane University (US)
  • Albert Einstein College of Medicine (US)
  • United States Department of Veterans Affairs (US)
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  • University of Mississippi Medical Center (US)
  • The Lundquist Institute (US)
  • The University of Texas Rio Grande Valley (US)
  • Henry Ford Health (US)
  • University of Arizona (US)
  • Brown University (US)
  • Vanderbilt University Medical Center (US)
  • University of North Carolina at Chapel Hill (US)
  • National Institutes of Health (US)
  • University of Alabama at Birmingham (US)
  • Mayo Clinic (US)
  • University of Pittsburgh (US)
  • Washington University in St. Louis (US)
  • University of Illinois Chicago (US)
  • University of Vermont (US)
  • Duke Medical Center (US)
  • Northwestern University (US)
  • The University of Texas Health Science Center at Houston (US)
  • National Jewish Health (US)
  • Taichung Veterans General Hospital (TW)
  • Baylor College of Medicine (US)
  • Weill Cornell Medicine (US)
  • New York Genome Center (US)
  • Children's Hospital of Philadelphia (US)
  • University of Mississippi (US)
  • Cleveland Clinic (US)
  • Columbia University (US)
  • Emmes (United States) (US)
  • Medical College of Wisconsin (US)
  • Stanford University (US)
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  • University of California, Los Angeles (US)
  • National Taiwan University Hospital (TW)
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  • National Health Research Institutes (TW)
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  • University of Wisconsin–Milwaukee (US)
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  • Beth Israel Deaconess Medical Center (US)
  • Stanford Medicine (US)
  • Regeneron (United States) (US)
Corresponding author
  • Kathiresan, Sekar
  • Natarajan, Pradeep
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2020-10-14
Volume
586
Issue
7831
Pages
763-768
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-020-2819-2
PMC
PMC7944936
OpenAlex
W3093370683
Cited by
733
References
54
Citations by year
2026: 101 · 2025: 142 · 2024: 149 · 2023: 115 · 2022: 124 · 2021: 97 · 2020: 5
FWCI
54.00
Type
journal article
Language
en
Update notices
correction (2021-03-11)
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • ScholarWorks @ UTRGV (The University of Texas Rio Grande Valley) (submittedVersion)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • American Heart Association (18SFRN34250007)
  • National Institutes of Health (1r01hl120393-01a1, 5p50hl118006-05, DP5OD029586, 5k01hl135405-04, UL1TR001863, 5r01hl113323-05)
  • National Institute on Aging (K01AG059898)
  • National Heart, Lung, and Blood Institute (R03HL154284, R01-HL120393, K01-HL135405, R01HL148050, R01HL143818, K01HL136700, R35HL135818, HHSN268201800001C, R01-HL113323, P50-HL-118006, P01HL132825, UG3HL151865, U01HL130114, DP2HL157540, F30HL149180, R01HL149836, U01HL089856, R01HL091357, R01HL138737, U01HL137162, R01HL117626, K08HL141601, R01HL055673, UH3HL151865, T32HL129982, R01HL133040, R01HL148565, R01HL139731)
  • National Human Genome Research Institute (UM1HG008895, R01HG009974)
  • National Cancer Institute (R35CA253125)
  • National Institute of General Medical Sciences (U54GM115428)
  • National Institute of Allergy and Infectious Diseases (R01AI132476)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords
clonal hematopoiesis of indeterminate potential, germline genetic variants, somatic mutations, hematopoietic stem cells, TET2, distal enhancers, aging, coronary artery disease, hematologic cancer, genetic susceptibility, TOPMed, African ancestry
MeSH terms
Cell Self Renewal, Tripartite Motif Proteins, Whole Genome Sequencing, Clonal Hematopoiesis, Adult, Africa, Aged, Aged, 80 and over, Black or African American, DNA-Binding Proteins, Female, Hematopoietic Stem Cells, Humans, Male, Middle Aged, Phenotype, Proto-Oncogene Proteins, United States, Genome, Human, Germ-Line Mutation, Genetic Predisposition to Disease, alpha Karyopherins, Black People, Intracellular Signaling Peptides and Proteins, Dioxygenases, National Heart, Lung, and Blood Institute (U.S.), Precision Medicine

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