Genetics & Genomics

June 4, 2024

Research raises hope for treating potentially lethal blood condition

Roughly 1 in 10 people over age 70 will develop CHIP, an explosive, clonal growth of abnormal blood cells that increases risk of blood cancers and death from cardiovascular, lung and liver disease.

Graduate student Taralynn Mack, left, pipettes a sample while Alexander Bick, MD, graduate student Hannah Poisner, and Celestine Wanjalla, MD, PhD, look on. Graduate student Taralynn Mack, left, pipettes a sample while Alexander Bick, MD, graduate student Hannah Poisner, and Celestine Wanjalla, MD, PhD, look on.

A multicenter study led by researchers at Vanderbilt University Medical Center has identified a set of circulating proteins and other factors associated with a common age-related and potentially life-threatening condition characterized by an “explosion” of abnormal blood cells.

The discovery, reported June 4 in the journal Nature Aging, may aid in the development of therapeutic targets and improved outcomes for patients diagnosed with this condition, called “clonal hematopoiesis of indeterminate potential” or CHIP, the researchers concluded.

Roughly 1 in 10 people over age 70 will develop CHIP, an explosive, clonal growth (hematopoiesis) of abnormal cells triggered by somatic (non-inherited) mutations in blood stem cells. CHIP increases by an estimated 40% the risk of death from cardiovascular, lung and liver disease, as well as other inflammatory conditions. 

“Over the past decade scientists have identified environmental factors that alter clonal expansion in animal experiments,” said the paper’s corresponding author, Alexander Bick, MD, PhD, assistant professor of Medicine at VUMC, whose team has developed methods for investigating what causes CHIP — and how it might be prevented.

“In this study, we tested whether these observations in fact were true in human patients,” he said.

According to one hypothesis, both DNA methylation, a biomarker for biological aging, and an inherited, germline risk for inflammation can lead to faster clonal expansion rates in patients with CHIP, increasing the risk for adverse outcomes.

To test their hypothesis, the researchers used PACER, a technique developed in the Bick lab to identify genes that, when expressed, drive clonal expansion.

DNA methylation is an “epigenetic” modification that does not change the underlying DNA sequence, but which can alter gene expression. With age, dividing cells acquire alterations, most of which are innocuous “passenger” mutations. But in the case of CHIP, some mutations drive the expansion of clones of abnormal blood cells.

Previously, scientists would measure clonal growth rate by comparing blood samples taken decades apart. Bick and his colleagues figured out a way to determine the growth rate from a single timepoint, by counting the number of passenger mutations.

“You can think of passenger mutations like rings on a tree,” Bick said. “The more rings a tree has, the older it is.”

The researchers applied PACER to estimate the CHIP expansion rate in 4,370 individuals from the Trans-Omics for Precision (TOPMed) program. Sponsored by the National Heart, Lung and Blood Institute of the National Institutes of Health, TOPMed integrates genomic and clinical data to help scientists advance the development of precision medicine.

As predicted, the analysis revealed an association between CHIP clonal expansion rates and DNA methylation (age-related alterations in gene expression), and with various “epigenetic clocks,” which estimate biological age based on predictable patterns of DNA methylation.

These clocks can predict time-to-death and time to diseases including cardiovascular disease and cancer based on DNA methylation-based markers for plasma proteins that are associated with metabolic syndrome and inflammation, and with genes associated with Alzheimer’s disease, oxidative stress, and other age-related conditions.

Surprisingly, the study did not confirm a previously identified association between the clonal expansion rate and inflammatory proteins or inflammatory conditions.

But it did identify four proteins in the bloodstream that were associated with the clonal expansion rate. These potentially targetable proteins, which have previously been characterized as promoters or suppressors of tumor growth, may be useful for further investigations of the mechanisms underlying CHIP expansion, the researchers concluded.

Researchers from 23 institutions across the United States and in Taiwan contributed to the study.

First authors of the paper were Taralynn Mack, a graduate student in Human Genetics at Vanderbilt, and Michael Raddatz, MD, PhD, a former MD/PhD student at Vanderbilt who currently is a cardiology fellow and physician-scientist at UCLA.

Other Vanderbilt coauthors were Yash Pershad, an MD/PhD student in Human Genetics, Benjamin Shoemaker, MD, MSCI, associate professor of Medicine, Division of Cardiovascular Medicine, and Dan Roden, MD, Senior Vice President for Personalized Medicine at VUMC, and the Sam L. Clark, MD, PhD Professor of Medicine, Pharmacology, and Biomedical Informatics.

Support was provided by the TOPMed program (NIH grants 3R01HL-117626-02S and R01HL-120393), a Burroughs Wellcome Foundation Career Award for Medical Scientists, Foundation Leducq, the Ludwig Center for Cancer Stem Cell Research, an American Society of Hematology Scholar Award, the NIH Director’s New Innovator and Early Independence Awards (grants DP2-HL157540 and DP5-OD029586, respectively), a Leukemia and Lymphoma Society Discovery Grant, and a Pew-Stewart Scholar for Cancer Research Award.