Determining which genes influence the risk of developing metabolic dysfunction–associated fatty liver disease (MASLD) among people with type 2 diabetes and obesity has been very difficult, but now researchers have finally cracked the code. The research shows that an overactive gene appears to increase fat deposition in the liver.
For many years, researchers have aimed to discover how genes influence the risk of developing MASLD.
However, they have had the problem that large genetic studies generally require data on many people, and this is not easy for people with MASLD, because determining the amount of fat in the liver requires magnetic resonance imaging (MRI).
Scanning the livers of 100,000 people, for example, would be very expensive, and genetic studies have therefore only been able to identify a few genes that influence the risk of MASLD.
However, researchers have discovered how to determine the amount of fat in the liver from blood tests, and they can then finally identify which genes determine whether an individual has a high or low risk of developing MASLD.
The research has been published in Hepatology.
“This provides new insight into how genes affect the accumulation of fat in the liver and how these genes also influence the development of other diseases,” explains a researcher behind the study, Peter Saliba-Gustafsson, Karolinska Institutet, Stockholm, Sweden.
New risk score for MASLD
The researchers first established that a risk score for MASLD can be determined based on new surrogate markers, including the presence of various liver enzymes and the amount of fat in the blood and body mass index (BMI).
Using the risk score for MASLD, the researchers searched data on hundreds of thousands of people from the UK Biobank for genetic predisposition for developing MASLD since the data for many of these people include blood test measurements, gene profiles and BMI.
“The data enabled us to avoid having to examine fat accumulation in the liver using MRI to scan many test subjects, since MRI is not carried out on a large scale. But we have easy access to blood samples from hundreds of thousands of people, and their genes have also been characterised. This type of study has been done before using only liver enzymes to indicate liver damage. Our risk score is better and more specific than just using the blood levels of these enzymes,” says Peter Saliba-Gustafsson.
Several genes influence the risk of MASLD
The researchers found that the genes VKORC1, TNKS, LYPLAL1 and GPAM influence the risk of developing MASLD, since their genetic variants are associated with a greater or lesser risk of developing disease related to the accumulation of fat in the liver.
The researchers then set out to investigate what these genes actually do.
In this part of the research, they used advanced CRISPR technology to knock out individual genes in individual liver cells in a petri dish and then investigate how this affected the overall genetic expression of the liver cells.
This revealed that VKORC1 is especially associated with an increased risk of developing MASLD. VKORC1 has traditionally been linked to the risk of developing type 2 diabetes and insulin resistance but has not previously been linked to MASLD.
Influences fat accumulation
Specifically, the research found that when VKORC1 is knocked out or mutated, this disturbs the metabolism of liver cells so that they cannot accumulate fat in the same way.
“When we knocked out this gene, the liver cells did not accumulate fat, and this means that we want a variant of this gene in the liver that is not very effective. However, we do not yet know whether high expression of this gene results from the liver cells accumulating more fat or whether higher expression forces the liver cells to accumulate more fat. However, we can conclude that lower activity in this gene causes the liver cells to accumulate less fat and that VKORC1 therefore influences fat accumulation in liver cells,” explains Peter Saliba-Gustafsson.
The researchers also studied RNA in the liver of people by using data from publicly available biobanks and found that the more VKORC1 RNA these people had in their liver, the more MASLD had progressed in relation to fat accumulation and inflammation in the liver – indicating a worse prognosis.
Influences blood coagulation
Another interesting perspective in the study is that the researchers have previously shown that VKORC1 is involved in the processes that control blood coagulation.
Research has previously shown that MASLD and disturbances in blood coagulation may be linked, but the mechanism has been unknown until now.
“Our data support the hypothesis that this gene links MASLD and disturbances in blood coagulation, and investigating this further will be interesting,” says Peter Saliba-Gustafsson, who elaborates that researchers have also only just scratched the surface of the genetic predisposition for the development of MASLD.
So far, researchers have only investigated the role of 10 to 15 genes of the hundreds if not thousands of genes associated with the risk of MASLD.
“Our next goal is to scale up our CRISPR studies to determine what happens in individual liver cells when we knock out each of these genes. Our studies also open new avenues for studying functional genetics in various diseases, since CRISPR can be used for other types of cells in studies of other diseases,” concludes Peter Saliba-Gustafsson.
