Context is known to influence many spheres. And now, researchers have found that a patients’ health context—that is, the other conditions a patient has—can determine whether a specific gene mutation is helpful or harmful. Researchers have revealed that a genetic mutation with a controversial connection to liver disease confers different levels of risk depending on whether patients have diabetes.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease, and can develop into nonalcoholic steatohepatitis (NASH) involving fat accumulation, damage, and inflammation in the liver. Known genetic variants explain only a modest fraction of the risk of developing NAFLD/NASH, and researchers disagree on the importance of certain mutations.

“The association of the glucokinase regulatory protein (GCKR)-rs1260326 mutation with NAFLD is widely debated,” says the first author. “This mutation appears to protect patients from diabetes and chronic kidney disease, but is associated with an increased risk of NAFLD and other diseases.”

To better understand the role of GCKR-rs1260326 in NAFLD/NASH, cells were taken from 24 donors and grown into tiny liver-like organs, called organoids. Feeding them extra fatty acids resulted in fat accumulation, inflammation, and insulin resistance, traits that are seen in the livers of patients with NASH. The connections between genetic variants and liver organoid features were then closely analyzed.

“The results were very clear,” states the senior author. “We found that the NAFLD/NASH risk connected to the GCKR-rs1260326 mutation in our organoid model was very high, despite it rarely being considered to be clinically significant.”

Organoids with two copies of the GCKR-rs1260326 mutation took up fat from their environment much more efficiently than other organoids, which explains how this mutation could make patients develop a fatty liver. Unexpectedly, analysis of real-life patient data showed that the level of liver inflammation in NASH patients with diabetes differed based on the presence or absence of the mutation: diabetic patients with two copies of the mutation had high levels of liver inflammation, while diabetic patients with no copies of the mutated gene showed only low levels of inflammation.

Furthermore, the researchers found that treating patients with metformin, a drug commonly used for diabetes, only worked when patients carried unmutated copies of GCKR. However, combined treatment with the drugs nicotinamide riboside and nitozoxanide improved the function of the liver organoids with two copies of the GCKR-rs1260326 mutation.

“This finding suggests a new treatment approach that could make a real impact in the lives of diabetic patients with the mutation who do not respond to standard medication,” states the senior author.

https://www.cell.com/cell/fulltext/S0092-8674(22)01250-8