TGen study identifies biomarkers of non-alcoholic fatty liver disease




Promising biomarkers for the progression of non-alcoholic fatty liver disease (NAFLD) were found in a study conducted by researchers at the Translational Genomics Research Institute (TGen), a subsidiary of City of Hope.

They identified differences in DNA methylation (mDNA) that accurately predicted the different stages of liver fibrosis in up to 94% of patients with NAFLD, according to the study published in the journal Clinical epigenetics.

NAFLD is the most common chronic liver disease in Western countries, characterized by accumulations of fat in the liver. This condition can include the development of fibrosis, which can be caused by methylation of DNA (mDNA) – a biological process in which methyl groups are added to DNA without changing its sequence.

“DNAm profiles can be used to identify distinct cell types in the liver and changes in the composition of cell types,” said Johanna DiStefano, PhD, Head of Diabetes and Fibrotic Diseases Unit at TGen. She is also one of the lead authors of the study.

Using samples collected by biopsy, the researchers examined the genomic data of 325 patients with NAFLD: 206 without apparent liver scars and 119 with varying levels of fibrosis. In its most severe form, NAFLD can progress to a condition called non-alcoholic steatohepatitis (NASH), and in turn lead to cirrhosis, liver cancer and death.

The researchers found that more severe fibrosis levels were associated with a gradual increase in the percentage of immune cells in the liver and a corresponding decrease in the percentage of epithelial cells, a type of cell that lines various body surfaces, including organs. such as the liver.

Karen Conneely, PhD, associate professor in the Department of Human Genetics at Emory University School of Medicine and lead author of the study, explained that the researchers also found that even after accounting for the differences in cell composition between individuals, mDNA levels at specific sites in the genome were decreased in patients with severe fibrosis.

The differences were striking enough that Nicholas Johnson, Emory’s PhD and lead author of the study, was able to develop a mDNA-based model at 28 genomic sites that could accurately predict fibrosis levels in 94% of patients. NAFLD in an independent test set.

“These results are consistent with mDNA as a mechanism underlying, or marking, fibrosis-related changes in cell composition, and demonstrate the potential of mDNA as a possible biomarker of NAFLD fibrosis,” said Xiumei Wu, PhD, TGen’s staff scientist in the DiStefano Lab, and one of the study’s authors.

For this study, samples were taken directly from the liver of patients via the relatively invasive use of biopsies. Taking advantage of the technology developed by TGen, they suggest that future samples could be obtained from circulating blood.

“Circulating mDNA has been suggested as a potential non-invasive biomarker of disease severity for NAFLD,” the researchers wrote. “These results suggest that our model could potentially predict NAFLD fibrosis in blood mDNA.”

The researchers suggest that future analysis could also be complemented by the use of single-cell RNA sequencing, a more precise method of analyzing genomic information, which has the potential to measure cell composition at higher resolution and to facilitate a better understanding of the relationship between NAFLD fibrosis, cell composition and mDNA.

“Overall, our investigation shows that mDNA provides information that is not only useful for understanding the underlying biology of NAFLD,” said DiStefano, “but can also serve as a clinical tool capable of independently diagnosing fibrosis. “


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