Germline genetics, disease, and exposure to medication influence longitudinal dynamics of clonal hematopoiesis

Germline genetics, disease, and exposure to medication influence longitudinal dynamics of clonal hematopoiesisClonal hematopoiesis of indeterminate potential (CHIP) occurs when a hematopoietic stem cell acquires a somatic driver mutation in a leukemia-associated gene, with a variant allele fraction (VAF) exceeding 2% in peripheral blood. 1 Higher VAF is associated with increased morbidity and mortality risk.[2][3][4][5] Identifying factors influencing clonal expansion rate is crucial for risk stratification in CHIP patients.Recent cost-effective targeted assays have enabled serial sequencing and longitudinal profiling of CHIP dynamics.6 We present the largest longitudinal analysis of CHIP mutational dynamics to-date, examining 3,000 individuals from the Vanderbilt BioVU biobank.Our findings reveal that CHIP growth rates vary significantly by driver gene and are influenced by germline variants and medication exposures.Additionally, we demonstrate that monitoring blood counts may be more informative for risk stratification than frequent resequencing in CHIP patients.We performed targeted, error-corrected sequencing on serial blood samples from 3,000 individuals in the Vanderbilt BioVU biobank, using custom-designed probes for 22 CHIP-associated genes (Online Supplementary Table S1; Online Supplementary Figure S1).Vanderbilt University Medical Center's Institutional Review Board oversees BioVU and approved this project (IRB #201783).Unique molecular identifiers (UMI) were used for error correction, excluding mutations detected from a single UMI.The mean coverage depth was 1,725x after de-duplication.CHIP mutations were called for variants with ≥100x total read depth, ≥3 variant allele reads, and >2% VAF in at least one blood draw.We identified 893 CHIP mutations in 711 individuals (Figure 1A).Participants' mean age at first draw was 70 years (range, 19-96), with a mean 5.7-year interval (range, 0.7-13) between samples.Mean VAF were 6.7% and 9.5% at first and second draws, respectively.Most individuals (79%) had a single CHIP mutation, 16% had two, and 4% had three or more (Figure 1B).DNMT3A and TET2 were the most frequently mutated genes.Of the 711 individuals, 74% had CHIP at both time points, while 26% had >2% VAF at only one draw, predominantly (78%) at the second draw.We modeled the growth rate r with a compound interest formula -1.SRSF2/SF3B1 (splicing factor) driver mutations exhibited the fastest average growth rate (~25% annually), while DNMT3A driver mutations showed the slowest rate (~7% annually) (Figure 1C).Seventy-eight percent of mutations increased in VAF (annual growth rate >1%), consistent with prior studies.5,7 Decreases in VAF (annual growth rate <-1%) were observed in 30% of

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