Is MASH Hereditary? What To Know About the Genetic Links

Metabolic dysfunction-associated steatohepatitis (MASH), previously known as non-alcoholic steatohepatitis (NASH), is a type of liver disease where fat build-up in your liver causes inflammation and damage.

Certain factors may increase your chances of developing MASH, including health conditions, diet, and lifestyle. Genetics and family history can play a role in developing MASH, too.

Genetics may have something to do with why someone develops MASH. Research has found several genetic variants that are associated with the development and progression of MASH. Genes that may increase the risk of developing MASH or influence how the disease progresses include:

• Patatin-like phospholipase domain-containing protein 3 (PNPLA3): PNPLA3 is a protein in the liver and fat tissues. A specific variant called PNPLA3 p.I148M may be strongly associated with MASH. It’s believed that when this variant produces more protein than it should, you can develop liver inflammation and fat accumulation.
• Transmembrane 6 superfamily member 2 (TM6SF2): This protein is found mainly in the liver and small intestine. The TM6SFS2 E167K variant causes defective production and secretion of very-low-density lipoprotein (VLDL) and cholesterol from liver cells, causing increased fat accumulation in the liver, which can lead to MASH.
• Glucokinase regulator (GCKR): This gene is found in the liver and helps regulate an enzyme (protein) called glucokinase, which keeps blood sugar levels in check. Several variants of the GCKR gene have been associated with increased risk of MASH among adults, as well as among children and adolescents with obesity. GCKR gene variants can also lead to MASH-related liver cancer.
• Membrane-bound O-acetyltransferase domain containing 7 (MBOAT7): This gene encodes an enzyme called lysophosphatidylinositol (LPI) acyltransferase that plays a key role in lipid (fat) metabolism in the liver. The MBOAT7 variant rs641738 can increase the risk of developing MASH.

Recent research has identified several other gene variants that may lead to the development of MASH. Most of these genes are believed to be tied to MASH for similar reasons, like their impact on inflammation. These genes include:

• Apolipoprotein E (APOE)
• Interleukin 17 receptor A (IL17RA)
• Glycerol-3-phosphate acyltransferase mitochondrial (GPAM or GPAT)
• Tribbles pseudokinase 1 (TRIB1)

Research has shown that first-degree relatives, such as parents, siblings, or children, of people with MASH have a higher risk of developing the condition, suggesting a possible genetic association.

A parental history of fat build-up in the liver is a risk factor for hepatic steatosis (fat accumulation in the liver), even in people who don’t have any metabolic issues like diabetes or obesity.

The prevalence of MASH varies among different ethnic groups. In the United States, people of Hispanic descent have the highest rates of MASH, followed by people of European descent. People of Asian descent may also be at greater risk of MASH. African Americans have the lowest prevalence.

Besides genes and family history, a few other common risk factors may lead to the development of MASH, including:

• Diet and lifestyle: Frequent consumption of low-nutrient, high-sodium, high-fat diets, along with reduced physical activity, may increase your chances of developing MASH. Dietary changes such as intermittent fasting, caloric restriction, and ketogenic diet with regular exercise can prevent MASH or delay its progression.
• Smoking: Tobacco smoke can speed up the development of MASH by promoting liver fat build-up and disrupting liver metabolism. 
• Air pollution: Long-term exposure to air pollutants, especially particulate matter 2.5 (PM2.5) can lead to liver damage through inflammation and oxidative stress, which can in turn increase the risk of developing MASH.
• Other health conditions: People with metabolic disorders like obesity or diabetes are at higher risk for developing MASH. These conditions may increase the risk by increasing fat accumulation in the liver, causing inflammation, and disrupting lipid metabolism.
• Age: The risk of developing MASH increases with age. Older age not only increases the risk of fat accumulation in the liver but can also increase the risk of disease progression to fibrosis (scarring) and liver cancer.  

MASH is an advanced form of fatty liver disease where you have fat and inflammation in the liver. Research suggests genes play a role in the development of MASH. These genes include PNPLA3, TM6SF2, GCKR, and MBOAT7. Along with genes, family history, and ethnicity may also play a role in the development of MASH.