Correlates and consequences of clonal hematopoiesis expansion rate: a 16-year longitudinal study of 6976 women

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased mortality and malignancy risk, yet the determinants of clonal expansion remain poorly understood. We performed sequencing at a depth of coverage of >4000× for CHIP mutations in 6976 postmenopausal women from the Women's Health Initiative (WHI) at 2 time points: the WHI baseline examination and ∼16 years later at the Long Life Study (LLS) visit. Among 3685 CH mutations detected at baseline (variant allele fraction [VAF] of ≥0.5%), 24% were not detected at LLS, 26% were micro-CH at LLS (0.5% ≤ VAF < 2%), and 50% were CHIP (VAF ≥ 2%). We confirmed that clonal expansion is highly dependent on initial clone size and CHIP driver gene, with SF3B1 and JAK2 mutations exhibiting the fastest growth rate. We identified germ line variants in TERT, IL6R, TCL1A, and MSI2 that modulate clonal expansion rate. Measured baseline leukocyte telomere length showed differential effects on incident CHIP risk, with shorter baseline leukocyte telomere length predisposing to incident PPM1D mutations and longer baseline leukocyte telomere length favoring incident DNMT3A mutations. We discovered that the IL6R missense variant p.Asp358Ala specifically impairs TET2 clonal expansion, supported by direct measurements of soluble interleukin-6 receptor and interleukin-6. Faster clonal growth rate was associated with increased risk of cytopenia, leukemia, and all-cause mortality. Notably, CHIP clonal expansion rate mediated 34.4% and 43.7% of the clonal hematopoiesis risk score's predictive value for leukemia and all-cause mortality, respectively. These findings reveal key biological determinants of CHIP progression and suggest that incorporating growth rate measurements could enhance risk stratification.

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Publication Details

Journal
Blood
Published
2025-06-11
DOI
https://doi.org/10.1182/blood.2025028417
Citations
11
Primary Topic
Hematopoietic Stem Cell Transplantation
Type
article
Field-Weighted Citation Impact
19.47

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article

Correlates and consequences of clonal hematopoiesis expansion rate: a 16-year longitudinal study of 6976 women

Md Mesbah Uddin, Alexander G. Bick, Eric A. Whitsel, Michael C. Honigberg et al.
11 citations
Blood
Hematopoietic Stem Cell Transplantation
19.47
article

Correlates and consequences of clonal hematopoiesis expansion rate: a 16-year longitudinal study of 6976 women

Md Mesbah Uddin, Alexander G. Bick, Eric A. Whitsel, Michael C. Honigberg, Taralynn Mack, Yash Pershad, Pradeep Natarajan, JoAnn E. Manson, Jason M. Collins, Pinkal M. Desai, Siddhartha Jaiswal, Alex P. Reiner, Liying Xue, Charles Kooperberg, V. M. Glaser, Urvashi Pandey, Jacob Otto Kitzman, Jeffrey Haessler, Kun Zhao, Elena Glick
article en
11 citations

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased mortality and malignancy risk, yet the determinants of clonal expansion remain poorly understood. We performed sequencing at a depth of coverage of >4000× for CHIP mutations in 6976 postmenopausal women from the Women's Health Initiative (WHI) at 2 time points: the WHI baseline examination and ∼16 years later at the Long Life Study (LLS) visit. Among 3685 CH mutations detected at baseline (variant allele fraction [VAF] of ≥0.5%), 24% were not detected at LLS, 26% were micro-CH at LLS (0.5% ≤ VAF < 2%), and 50% were CHIP (VAF ≥ 2%). We confirmed that clonal expansion is highly dependent on initial clone size and CHIP driver gene, with SF3B1 and JAK2 mutations exhibiting the fastest growth rate. We identified germ line variants in TERT, IL6R, TCL1A, and MSI2 that modulate clonal expansion rate. Measured baseline leukocyte telomere length showed differential effects on incident CHIP risk, with shorter baseline leukocyte telomere length predisposing to incident PPM1D mutations and longer baseline leukocyte telomere length favoring incident DNMT3A mutations. We discovered that the IL6R missense variant p.Asp358Ala specifically impairs TET2 clonal expansion, supported by direct measurements of soluble interleukin-6 receptor and interleukin-6. Faster clonal growth rate was associated with increased risk of cytopenia, leukemia, and all-cause mortality. Notably, CHIP clonal expansion rate mediated 34.4% and 43.7% of the clonal hematopoiesis risk score's predictive value for leukemia and all-cause mortality, respectively. These findings reveal key biological determinants of CHIP progression and suggest that incorporating growth rate measurements could enhance risk stratification.

BloodVol. 146(9)
Broad Institute (US), University of North Carolina at Chapel Hill (US), Brigham and Women's Hospital (US), Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa (ZA), NewYork–Presbyterian Hospital (US), Harvard University (US), Palo Alto University (US), University of Washington (US), Cornell University (US), University of Michigan (US), Massachusetts General Hospital (US), Fred Hutch Cancer Center (US), Presbyterian Hospital (US), Michigan United (US), Weill Cornell Medicine (US), Vanderbilt University Medical Center (US), Stanford University (US)
U.S. Department of Health and Human Services, Alexander and Margaret Stewart Trust, National Institutes of Health, National Heart, Lung, and Blood Institute
Openalex Percentile: Top 1%
Hematopoietic Stem Cell Transplantation
19.47
DOIOpen Access PDFOpenAlex
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