Circulating DNA May Be Biomarker of Rapidly Progressing IPF: Study

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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People with rapidly progressing idiopathic pulmonary fibrosis (IPF) have significantly higher levels of circulating cell-free DNA (ccfDNA) than those with slower disease progression and healthy people, a small study shows.

In addition, ccfDNA levels, which have been suggested to contribute to IPF, were found to be associated with changes in several metabolic pathways that are known to be affected in people with IPF.

These findings suggest that circulating DNA may be a biomarker of IPF progression and severity and a potential therapeutic target of the disease, but further studies are needed to confirm this, the researchers noted.

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The study, “Association of circulating cell-free double-stranded DNA and metabolic derangements in idiopathic pulmonary fibrosis,” was published in the journal Thorax.

While the cause of IPF and the triggers of disease progression remain unclear, increasing evidence suggests that circulating cell-free DNA contributes to the disease’s development. Cell-free DNA consists of short DNA fragments released into circulation from dying cells.

A previous study led by a team of researchers in the U.S. and South Korea showed that AIM2, a DNA sensor inside cells, plays a critical role in IPF and that it is regulated by glucose, or sugar, metabolism.

AIM2, part of the immune system’s first line of defense, recognizes DNA of microbial or host origin inside cells. Upon recognition, AIM2 forms a multiprotein complex called inflammasome that drives the production of inflammatory molecules and subsequent cell death.

Now, the same team evaluated the blood levels of ccfDNA in 98 IPF patients (59 rapid progressors and 39 slow progressors) and 28 healthy individuals (used as controls) and assessed whether these levels were linked to metabolic pathways.

All patients had participated in a previous observational clinical trial focused on identifying potential biomarkers of IPF progression (NCT01071707). Their mean age ranged from 64 to 66, and more than 69% smoked. Controls had a mean age of 61.

Results showed ccfDNA levels were significantly higher in patients with rapidly progressing IPF compared with slow progressors and healthy controls, whose levels were comparable.

When looking at nearly 800 byproducts of metabolic processes, the team found that increased ccfDNA levels were associated with higher levels of 73 metabolites and lower levels of 59 metabolites.

Two distinct groups of metabolites were identified based on ccfDNA levels, and 15 metabolic pathways showed the highest number of metabolites linked to circulating DNA.

Specifically, ccfDNA levels were significantly associated with changes in metabolic pathways of amino acids (the basic units of proteins), fatty molecules, and energy. Several of these pathways were previously linked to IPF or processes known to be involved in the disease, such as inflammation, scarring, and cell death.

These findings highlight ccfDNA “as a potential biomarker for IPF disease progression and severity and also as a mediator of IPF disease progression by modulation of specific metabolic pathways,” the researchers wrote.

While this observational study cannot establish a cause-effect relationship between ccfDNA and metabolic changes, the team noted that there is evidence suggesting that metabolic reprogramming regulates immune responses dependent on DNA sensors such as AIM2.

Future studies “may better elucidate the role of [ccfDNA] and metabolic [changes] both as possible biomarkers and as targets for therapeutics in IPF,” the researchers wrote.

They also noted that the source of ccfDNA in people with IPF remains unclear, but a previous study suggested mitochondria as a major source. Mitochondria are the small cell compartments responsible for energy production, and their dysfunction has been associated with IPF.