Multiomics studies have found clues to the diagnosis and treatment of nonalcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a growing health problem, with a global prevalence of up to 25%.

Nonalcoholic fatty liver disease (NAFL) is the first stage of NAFLD, after which it can progress to nonalcoholic steatohepatitis (NASH).

NASH can progress to cirrhosis and hepatocellular carcinoma
.
NAFLD is difficult to diagnose and monitor, and there is currently no reliable treatment
.
Therefore, it is important to
identify potential drug targets and biomarkers.

A new study led by Icelandic firm deCODE Genetics suggests that protein profiles from plasma samples may help distinguish NAFLD from other forms of liver disease and provide biological clues that could inform future treatments
.
The results were published this week in
the journal Nature Genetics.

Co-corresponding authors Gardar Sveinbjornsson and Kari Stefansson of deCODE Genetics and colleagues write: "This study provides insights
for non-invasive testing of nonalcoholic fatty liver disease and the development of new therapies.
”

The researchers utilized 9,491 clinical cases and proton density fat fractions (PDFFs) extracted from more than 36,100 magnetic resonance images, plus a NAFLD-focused GWAS meta-analysis
.
They traced 18 NAFLD-associated variants and 4 cirrhosis-associated variants
from 17 sites in the genome.

They then analysed 4,907 plasma proteins from nearly 36,000 Icelanders and 1,459 proteins from nearly 47,200 UK biobank participants to identify multiple proteins
involved in disease progression.
They noted that a relatively wide range of proteins contribute to the progression of NAFLD, including those encoding and regulatory variants
involved in lipid metabolism processes.

Through further GWAS and multiomics analysis, the researchers compared genetic variants that cause nonalcoholic fatty liver disease, cirrhosis, or hepatocellular carcinoma, as well as risk variants
associated with other traits or diseases.

They also tracked rare loss-of-function mutations in the mitochondrial enzyme-coding genes MTARC1 and GPAM, which appear to reduce the risk of nonalcoholic fatty liver disease in Icelandic populations, suggesting that inhibition of MTARC1 or GPAM can treat nonalcoholic fatty liver disease or steatohepatitis
.

"We demonstrated the differential effects of NAFLD risk alleles on other diseases and traits, including blood lipids and proteins, and showed that plasma proteomics profiles hold promise for staging NAFLD
," the authors write.
”

In addition, the researchers found that they could use protein profiles in individual plasma, genetic risk scores (GRS) for liver disease, and characteristics such as sex, age, and body mass index to distinguish cases
of nonalcoholic fatty liver disease from cirrhosis through computational analysis.
For example, patients with cirrhosis tend to have higher than normal levels of platelet reactive protein 2 (THBS2), while aminoacylase 1 (ACY1) is often associated
with nonalcoholic fatty liver disease.

"We designed plasma protein-based models that excelled at distinguishing between nonalcoholic fatty liver disease and cirrhosis," the authors explain, noting that "plasma protein levels promise to be a noninvasive tool for diagnosing and monitoring disease, while genetic risk scores for liver disease are associated
with lifetime risk.
" ”

Original text search

Sveinbjornsson, G.
, Ulfarsson, M.
O.
, Thorolfsdottir, R.
B.
et al.
Multiomics study of nonalcoholic fatty liver disease.
Nat Genet (2022).
https://doi.
org/10.
1038/s41588-022-01199-5