# Clonal Hematopoiesis in Healthy Individuals from Families with Early OnsetCoronary Artery Disease

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $809,064

## Abstract

Clonal hematopoiesis (CH) occurs with aging and is associated with increased mortality, a 10-fold increase of
incident cancers, and a >2 fold increase in coronary artery disease (CAD) and stroke. In CH a significant
proportion of circulating leukocytes are derived from a single dominant hematopoietic stem cell (HSC) lineage.
Somatic mutations in oncogenic driver and other genes may be responsible. CH is also associated with
shortened leukocyte telomere length (LTL) and accompanies biological aging and its effects, independent of
chronological age. Healthy first degree relatives from families with early-onset CAD demonstrate premature
aging cardiovascular phenotypes and bear a risk for incident CAD that is 2-12 times that of the general
population. These early-onset CAD families have highly heritable shortened LTL at young ages, and higher
rates of cancer. They may also have an increased prevalence of CH for their age, possibly contributing
mechanistically to CAD risk. We posit that populations with increased genetic susceptibility to early CAD and
shorter telomeres exhibit early-onset biological aging and have a higher prevalence of clinically silent CH,
which in turn may contribute to both atherosclerosis and cancer risk. No studies have investigated this
hypothesis in families with early-onset CAD, a putatively highly susceptible population. Our hypothesis is that a
family history of early CAD conveys a higher prevalence of CH and shorter LTL for age, contributing
mechanistically to a potent atherosclerosis substrate, with greater CAC score and higher rates of incident CAD.
We will determine the prevalence of CH in 1610 subjects from GeneSTAR, healthy siblings, offspring or
parents of probands with CAD < 60 years of age, using whole genome sequencing. We will determine whether
CH is related to shortened LTL, to CAD events, and to CAC scores, and further whether the prevalence of CH
is greater by age in subjects from families with and without early-onset CAD history in population studies
(Framingham Heart Study, Multiethnic Study of Atherosclerosis, Jackson Heart Study, and the Atherosclerosis
in Communities Study) in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program, of which
GeneSTAR is a member. We will identify germline and somatic variants associated with LTL and determine the
extent to which these are a function of family history of early CAD. Variants in candidate genes known to
regulate LTL, including telomerase genes and shelterin genes will be given priority in the analysis. We are also
examining increments in CH mutations and the LTL attrition rate over 6-20 years in the GeneSTAR families.
For the highest priority genetic variants, we will ascertain functional significance as potential drivers of CH
using gain-of-function (over-expression) and loss-of-function (gene silencing) approaches to assess their effect
on proliferation and clonal expansion in cellular and in vivo murine models, and effects on atherosclerosis in
Ldl...

## Key facts

- **NIH application ID:** 9923751
- **Project number:** 5R01HL143818-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Lewis C Becker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $809,064
- **Award type:** 5
- **Project period:** 2019-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9923751

## Citation

> US National Institutes of Health, RePORTER application 9923751, Clonal Hematopoiesis in Healthy Individuals from Families with Early OnsetCoronary Artery Disease (5R01HL143818-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9923751. Licensed CC0.

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