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AGBT: cfDNA Methylation Profiling Shows Promise as Blood Biomarker for Congestive Heart Failure

HOLLYWOOD, Fla. – Researchers from The Hebrew University of Jerusalem and their collaborators are harnessing cell-free DNA (cfDNA) methylation signals as potential biomarkers for cardiac diseases.

Presenting preliminary results from his group in a Tuesday evening talk at the Advances in Genome Biology and Technology annual meeting held here this week, Hebrew University's Netanel Loyfer showed that deep whole-genome bisulfite sequencing of cfDNA using the Ultima Genomics platform has the potential to become a non-invasive liquid biopsy assay to help monitor patients with congestive heart failure.

"What we are trying to do is us[e] cell-free DNA fragments as evidence of remote cell-death events," said Loyfer. Methylation patterns of the cfDNA molecules provide a window for scientists to infer their contributing cell types, he added.

Loyfer's group has been collaborating with Grail to establish a DNA methylation atlas of normal human cell types. In that effort, the researchers deployed deep whole-genome bisulfite sequencing using PE150 reads at an average sequencing depth of 30X on 39 human cell types purified using fluorescent-activated cell sorting (FACS) from 205 healthy tissue samples.

The resulting atlas, described in a Nature study published in January, contains 28 million methylation sites encompassing cells from the immune, blood, respiratory, cardiac, and other systems. That database "provides an essential resource for study of gene regulation and disease-associated genetic variants and a wealth of potential tissue-specific biomarkers for use in liquid biopsies," the study authors noted.

"Now that we have the methylation signatures for most of the cell types that we think are likely to be found in plasma," Loyfer said, "we want to use them for the deconvolution task."

To that aspiration, his group has developed a computational fragment-level deconvolution algorithm to help analyze DNA methylation sequencing data, and has introduced wgbstools, a machine-learning software suite to help process, visualize, and analyze whole-genome bisulfite sequencing data.

Attracted by its high throughput and low sequencing cost, Loyfer's team also explored using the new platform from Ultima Genomics to perform whole-genome bisulfite sequencing on the cfDNA samples for their study.

To validate the new sequencing technology, the researchers performed fragment-level analysis on four different datasets of normal plasma samples collected from labs in different parts of the world using the Illumina and Ultima platforms.

The results looked "more or less the same," Loyfer said, "which is great news for our research question." 

Encouraged by this, the researchers further sought to harness these signals for clinical applications, such as discovering biomarkers that could be used to develop a liquid biopsy assay for congestive heart disease.

A chronic condition, congestive heart disease affects more than 60 million people worldwide, and there is an unmet need for biomarkers to help detect progression and guide treatment, Loyfer noted.

To that end, Loyfer's team has initiated a pilot study in which they collected 18 plasma samples from patients with congestive heart disease, 13 samples from myocardial infarction patients, as well as 17 normal plasma samples.

They performed deep whole-genome bisulfite sequencing on the cfDNA harvested from these samples using the Ultima platform and carried out unbiased deconvolution to examine the contributing cell types in different groups.

Loyfer said that a preliminary analysis revealed that there was a "significant increase" in endothelium cells in myocardial infarction patients post-angioplasty. More interestingly, he noted, when it comes to patients with congestive heart disease, the data indicated a selective elevation of endothelial cfDNA for those with an ischemic etiology.

Although the investigators are still not sure of the reason for this correlation, previous studies have shown that dysfunction in the cardiac endothelium is correlated with the prognosis of congestive heart failure and is associated with hospitalization and disease transgression.

"There is reason to be optimistic," Lofyer said. 'We think we may have found a useful biomarker for this disease."