# Establishing the dynamics of lymphoid clonal hematopoiesis and its aging-related disease consequences

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $703,426

## Abstract

Project Summary
With age, dividing cells acquire DNA mutations. A small number of these somatic mutations confer a selective
advantage leading to a clonal proliferation of cells harboring the somatic mutation. In blood, this process is
termed ‘clonal hematopoiesis’. These mutations include both point mutations in cancer driver genes (eg. clonal
hematopoiesis of indeterminate potential ‘CHIP’) and megabase-scale deletions, duplications and copy-neutral
loss-of-heterozygosity (eg, mosaic chromosomal alterations, ‘mCAs’). CHIP and mCAs have each been
detected in ~5% of individuals over 60. While both predict shorter lifespans, CHIP leads to a myeloid biased
stem cell differentiation while mCAs lead to a lymphoid biased stem cell differentiation. As a result, CHIP and
mCAs have distinct disease associations with infection, cardiovascular disease, cancer and other diseases of
aging. Although CHIP has been an area of significant research activity, multiple gaps persist in our knowledge
of mCAs and their impacts on aging and population health. mCA clones that expand to make up a larger
proportion of the blood predict worse health consequences. However, we do not know why some mCA clones
but not others expand, what factors predict the rate of clonal expansion and how rate of expansion associates
with disease outcomes. Overall, we hypothesize that mCAs with higher rates of clonal expansion confer a
greater impact on health and that the propensity to expand has genetic and environmental underpinnings that
are mediated through gene expression. A barrier to addressing this gap is a paucity of large well-annotated
collections of longitudinally-sampled blood. Fortuitously, our team has two recent accomplishments that enable
us to address this gap: 1) a survey of mCAs in 67,000 whole genomes and 2) development of a novel
computational method to estimate the rate of mCA expansion from single timepoints. In Aim 1, we will
measure the rate of mCA expansion by leveraging unique serial blood samples (collected up to 19 years apart)
from 729 individuals with mCAs from three deeply phenotyped cohorts. In Aim 2, we will refine our method for
clonal expansion rate estimation and apply this method at population scale to estimate mCA clonal expansion
rates in 1.3 million individuals from several diverse cohorts. We will identify genetic and environmental factors
predisposing to clonal expansion and establish the relationship between mCA clonal expansion and disease. In
Aim 3, we will analyze bulk and single-cell RNA-sequencing to ascertain the cell type specific biological impact
of mCAs and identify pathways leading to clonal expansion. Our multidisciplinary team with deep expertise in
computational genomics, statistics, hematology and human epidemiology is uniquely poised for success in this
effort. Successful execution of our aims will inform risk models to stratify individuals with mCAs for
personalized prevention, such as interventions or enhanced screening, and iden...

## Key facts

- **NIH application ID:** 10913473
- **Project number:** 5R01AG083736-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Paul L. Auer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $703,426
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10913473

## Citation

> US National Institutes of Health, RePORTER application 10913473, Establishing the dynamics of lymphoid clonal hematopoiesis and its aging-related disease consequences (5R01AG083736-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10913473. Licensed CC0.

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