# Clonal Hematopoiesis in the Women's Health Initiative

> **NIH NIH R01** · FRED HUTCHINSON CANCER CENTER · 2024 · $815,981

## Abstract

PROJECT SUMMARY
Clonal hematopoiesis of indeterminate potential (CHIP) is a common, age-related condition in which
hematopoietic stem cells in the bone marrow undergo somatic mutations that lead to overgrowth (“clones”) of a
genetically distinct subpopulation of blood cells. Evidence is mounting that CHIP is causally related through pro-
inflammatory signaling to the occurrence of atherosclerotic cardiovascular disease (CVD) and heart failure (HF).
Our preliminary data from the Women’s Health Initiative (WHI) suggests that CHIP may be associated specifically
with risk of incident heart failure with preserved ejection fraction (HFpEF), a HF subtype characterized by chronic,
low-grade inflammation. Prior studies of CHIP were cross-sectional and limited information is available on
behavioral/lifestyle, environmental, and heritable risk factors for CHIP progression. The large (N~161,000), multi-
ethnic, prospective WHI, which enrolled post-menopausal women during 1993-1998 is particularly well-suited to
address these limitations because of its longitudinal design, availability of extensive exposure and phenotype
data, and ongoing surveillance of incident disease/mortality among older women, including HFpEF and HFrEF.
In our competing renewal application, we will continue to utilize the unique resources of the WHI, as well as other
cohorts and large biobanks, to address several questions of high clinical importance related to the epidemiology
of CHIP, heart failure, and its aging-related comorbidities. During the current funding period, a subset of ~7,000
of the original WHI cohort who underwent a subsequent examination and blood sampling in 2012 (ranging from
14 to 19 years after WHI enrollment) as part of the WHI Long Life Study (LLS)-1 exam have undergone deep
targeted CHIP sequencing of blood samples collected at two time points, baseline and LLS-1. We plan to expand
this longitudinal CHIP resource by sequencing another 5,000 surviving WHI participants using samples collected
at the upcoming LLS-2 exam in 2023-2024 including a third time point in 3,000 WHI LLS-1 participants. Together
these data motivate further studies to investigate risk factors and specific driver mutations associated with CHIP
clonal expansion over a ~30-year period spanning WHI baseline through LL2-2 exams (Aim 1). Validation of any
association findings with CHIP progression will be facilitated in additional data sets with WGS using a newly
developed in-silico PACER single timepoint approach. In Aim 2, we will perform targeted CHIP sequencing in a
large case-cohort of incident HF adjudicated during follow-up (N>5,000 WHI cases and the same number of
matched controls) to further assess associations between baseline CHIP and incident heart failure subtypes
(HFpEF vs. HFrEF) and replicate findings using additional HF and echo/MRI-based LV function data in other
cohorts. In addition, we will explore whether any CHIP-HF associations are modified by other aging-related risk
factors...

## Key facts

- **NIH application ID:** 10882554
- **Project number:** 2R01HL148565-06A1
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** ALEXANDER P REINER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $815,981
- **Award type:** 2
- **Project period:** 2019-07-15 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882554

## Citation

> US National Institutes of Health, RePORTER application 10882554, Clonal Hematopoiesis in the Women's Health Initiative (2R01HL148565-06A1). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10882554. Licensed CC0.

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