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 >4,000x depth of coverage for CHIP mutations in 6,986 postmenopausal women from the Women's Health Initiative at two timepoints approximately 15 years apart. Among 3,685 mutations detected at baseline (VAF ≥ 0.5%), 50% progressed to CHIP (VAF ≥ 2%) at follow-up. 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 germline 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.

A.G.B. has received honoraria for advisory board membership from, and holds equity in, TenSixteen Bio. P.N. reports research grants from Allelica, Amgen, Apple, Boston Scientific, Genentech / Roche, and Novartis, personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Bristol Myers Squibb, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Esperion Therapeutics, Foresite Capital, Foresite Labs, Genentech / Roche, GV, HeartFlow, Magnet Biomedicine, Merck, Novartis, Novo Nordisk, TenSixteen Bio, and Tourmaline Bio, equity in Bolt, Candela, Mercury, MyOme, Parameter Health, Preciseli, and TenSixteen Bio, and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work.

This work was supported by NIH grants DP5 OD029586 and R01 AG088657, a Burroughs Wellcome Fund Career Award for Medical Scientists, an E.P. Evans Foundation grant, a RUNX1 Research Program grant, a Pew Charitable Trusts and Alexander and Margaret Stewart Trust Pew-Stewart Scholar for Cancer Research award (A.G.B.); NIH grant T32 GM007347 (Y.P.); and NIH grants R01 HL148565 (A.P.R., E.A.W). The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, 75N92021D00005.

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Human samples were obtained with informed consent. Fred Hutchinson Cancer Center Institutional Review Board (IRB #10186) reviewed our study and gave ethical approval for this work

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All data produced in the present study are available online via the WHI dbGaP accession number (phs000200.v12.p3).