A tiny change in DNA may be enough to cause a common form of fatty liver disease in some people, according to research from Mayo Clinic.
The discovery could help scientists better understand why liver disease sometimes develops in people who do not have the usual risk factors.
The condition is called metabolic dysfunction-associated steatotic liver disease, or MASLD. It was previously known as nonalcoholic fatty liver disease and occurs when too much fat collects inside the liver.
MASLD is extremely common and is estimated to affect roughly one-third of adults worldwide. Many people have few or no symptoms at first, but the disease can become more serious if inflammation and liver damage develop.
A more advanced form is called metabolic dysfunction-associated steatohepatitis, or MASH. Over time, repeated liver injury can produce scar tissue, known as fibrosis, and severe scarring can eventually lead to cirrhosis, liver failure, or liver cancer.
Doctors have traditionally linked MASLD with a combination of genetic and metabolic factors. Obesity, type 2 diabetes, abnormal cholesterol levels, diet, and physical inactivity can all increase the risk, although the disease can also occur in people without these problems.
The new research suggests that genetics may sometimes play a much more direct role. Scientists identified a rare change in a gene called MET that appeared capable of disrupting the liver’s normal control of fat.
The study began with a woman and her father who both had MASH despite lacking several of the risk factors usually associated with the disease. This unusual family pattern led researchers to investigate whether an inherited genetic change could explain their liver problems.
The team, led by Dr. Filippo Pinto e Vairo at Mayo Clinic’s Center for Individualized Medicine, examined more than 20,000 genes. They discovered a previously unreported change involving a single part of the DNA code in the MET gene.
MET provides instructions for a protein involved in important cell processes, including liver growth and repair. The researchers suspected that the newly discovered change prevented this system from working normally and affected the way liver cells handled fat.
To investigate further, the Mayo Clinic scientists worked with researchers at the Medical College of Wisconsin, including a team led by Dr. Raul Urrutia. Laboratory studies showed that the genetic change altered normal MET activity and disturbed processes involved in fat control inside liver cells.
When fat builds up excessively in the liver, it can make the organ more vulnerable to inflammation and injury. If this damage continues for years, scar tissue may gradually replace healthy liver tissue and interfere with the liver’s many essential jobs.
The researchers then examined whether rare MET changes could be found in a much larger population. They used information from Tapestry, a large Mayo Clinic research project that has collected genetic data from more than 100,000 people.
Among nearly 4,000 participants with MASLD, about 1% carried rare changes in MET. Some changes affected the same region of the gene involved in the original family, providing additional evidence that problems with MET may contribute to liver disease in a small group of patients.
This does not mean that a MET mutation explains most cases of fatty liver disease. MASLD has many possible causes, and lifestyle, metabolism, other genes, age, and overall health can all influence who develops the condition and how quickly it progresses.
However, the discovery shows that a disease that is common in the population can occasionally have a rare and powerful genetic cause. Identifying these patients could become important because their disease may develop differently from liver disease mainly associated with metabolic risk factors.
The findings also demonstrate the potential of personalized medicine. In the future, genetic testing could help doctors identify the biological reason for liver disease in certain patients and possibly choose treatments based on that cause.
Researchers will need to study more families and larger groups of patients to understand how strongly different MET changes affect disease risk. Scientists will also need to determine whether treatments aimed at the MET pathway could prevent or slow liver damage.
The study was published in the journal Hepatology. While the discovery is still at an early stage, it provides a striking example of how a change in a single piece of DNA can reveal new clues about a disease affecting millions of people.
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