# Clonal hematopoiesis and risk of peripheral artery disease

> **NIH VA IK2** · VETERANS ADMIN PALO ALTO HEALTH CARE SYS · 2023 · —

## Abstract

Peripheral artery disease (PAD) is a leading cause of cardiovascular morbidity and mortality worldwide, with a
particularly high burden among the Veteran population. Within the last decade, the age-related acquisition of
somatic mutations in hematopoietic stem cells have been associated with an increased risk of adverse clinical
outcomes and overall mortality. This new phenomenon, termed Clonal Hematopoiesis (CH), promotes an
overrepresentation of leukocytes derived from a single clone throughout peripheral blood. Previously, most CH
investigation has focused on a form of CH caused by “candidate driver” mutations in the leukemogenic genes
DNMT3A, TET2, JAK2, and ASXL1, termed Clonal Hematopoiesis of Indeterminate Potential (CHIP). CHIP
has been shown to be associated with an increased risk of hematologic malignancy, coronary artery disease,
and overall mortality. More recently, it has become evident that other forms of CH occur in human leukocytes
without “candidate driver” mutations that also predispose to increased mortality. However, whether any form of
CH is associated with increased risk of PAD remains unknown. In Aim 1, we will generate a somatic genomic
map of CH across multiple genetic biobanks, including the Million Veteran Program (MVP). We will perform
somatic variant detection for CHIP and two other forms of CH without candidate driver mutations - Clonal
Hematopoiesis with Unknown Drivers (CHUD) and mosaic Chromosomal Alterations (mCAs) - in over 350,000
individuals of diverse ancestries. Notably, current CHUD detection methods remain highly variable, and we will
develop novel techniques to identify CHUD carriers through machine learning. In Aim 2, we will test the
association of diverse forms CH with incident PAD events using Cox proportional hazards models. We will then
extend this analysis to incident, severe PAD events, focusing on chronic limb threatening ischemia, lower
extremity revascularization, and major limb amputation events and their relationship to CH. In Aim 3, we will
assess whether CH in all forms causally relates to PAD and identify genetic and non-genetic modifiers of CH-
associated PAD risk. First, we will use a Mendelian randomization framework and previously identified
germline CH risk variants to test the hypothesis that CH causally relates to PAD. Next, among individuals
without clinical PAD at enrollment, we will test whether individual genetic variants, particularly those that confer
risk of atherosclerosis or inflammation, modify risk of CH-associated PAD. Lastly, we will test whether other
non-genetic PAD risk factors alter this risk, with a particular focus on whether being a member of a minority
population modifies CH incidence and CH-associated PAD risk. Successful completion of this project will help
to elucidate the biology of the CH-PAD association and identify individuals at the highest risk of severe PAD.
These results will lay the groundwork for developing tailored strategies for the prevention of ...

## Key facts

- **NIH application ID:** 10653685
- **Project number:** 5IK2BX005759-02
- **Recipient organization:** VETERANS ADMIN PALO ALTO HEALTH CARE SYS
- **Principal Investigator:** Derek Klarin
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-07-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10653685

## Citation

> US National Institutes of Health, RePORTER application 10653685, Clonal hematopoiesis and risk of peripheral artery disease (5IK2BX005759-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10653685. Licensed CC0.

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