MASLD (formerly NAFLD) is one of the most common forms of chronic liver disease globally. It is defined by the buildup of excess fat in liver cells in individuals who consume little alcohol and have at least one metabolic risk factor. While poor diet and lifestyle are primary contributors, research increasingly demonstrates that a person’s genetic makeup plays a measurable role in susceptibility. The interaction between environment and inherited risk ultimately determines who develops MASLD and who progresses to its more severe forms.
Understanding Non-Genetic Drivers of Fatty Liver Disease
The vast majority of MASLD cases are directly linked to metabolic health and lifestyle factors, which are the non-inherited drivers of the condition. These factors promote the storage of fat in the liver. Conditions like obesity, Type 2 diabetes, and insulin resistance are strongly associated with steatosis, or fat accumulation in the liver.
A high intake of refined sugars, particularly fructose, and excess calories contributes significantly. This diet leads to the liver converting excess carbohydrates into fat through a process called de novo lipogenesis. When the body cannot manage blood sugar effectively or has high levels of circulating lipids (dyslipidemia), the liver becomes overwhelmed, leading to fat buildup.
These environmental and metabolic issues drive the current MASLD epidemic. For many, addressing these acquired risk factors through weight loss and dietary changes is sufficient to slow or even reverse liver damage.
The Concept of Inherited Susceptibility
Although lifestyle factors are powerful determinants, MASLD is rarely a simple matter of diet and weight alone. Scientific evidence confirms the condition has a significant hereditary component, meaning genes influence the likelihood of development. MASLD is not inherited in a simple, single-gene pattern, but rather through a complex mechanism called polygenic risk.
Polygenic risk means that multiple, independent genes each contribute a small amount to the overall risk. A combination of these small genetic risk factors determines a person’s underlying susceptibility. Studies of first-degree relatives (parents and siblings) show they can have an up to 12-fold increased risk of developing MASLD compared to the general population.
Twin studies estimate the heritability of hepatic steatosis (liver fat) to be between 35% and 61%. This high heritability suggests that even when twins share the same environment, genetic differences account for a substantial portion of the variation in liver fat development. Genetics acts as a susceptibility factor, influencing how easily the liver is damaged when exposed to common metabolic stressors.
Specific Genes That Increase Fatty Liver Risk
The strongest genetic predictor identified so far is a common variant in the PNPLA3 gene, specifically the I148M mutation. This gene provides instructions for making a protein that resides on the surface of lipid droplets within liver cells. The variant impairs the protein’s ability to break down triglycerides, leading to increased fat accumulation inside the hepatocytes.
Individuals who inherit two copies of this variant have a significantly higher risk of developing MASLD. They are also more likely to progress to the severe form, metabolic dysfunction-associated steatohepatitis (MASH), and advanced scarring (fibrosis). The PNPLA3 variant primarily influences fat storage in the liver without necessarily causing widespread metabolic issues like high cholesterol.
Another important variant is found in the TM6SF2 gene, which is strongly associated with increased liver fat content and a higher risk of advanced fibrosis. This gene regulates the secretion of very-low-density lipoproteins (VLDL), which transport fat out of the liver. The risk variant impairs this secretion process, trapping triglycerides inside the liver.
These variants are often combined into a polygenic risk score, offering a comprehensive assessment of inherited risk. The presence of these factors means an individual may develop severe liver disease even if they are not significantly overweight, a phenomenon called “lean MASLD.” This highlights how genetic background dictates fat handling and storage in the liver.
Screening and Management for Inherited Risk
Individuals with a strong family history of MASLD, especially if relatives have advanced liver disease or cirrhosis, require a proactive approach to health. The most effective management remains the early adoption of lifestyle interventions, even without significant weight gain. This includes dietary changes and consistent exercise to maintain metabolic health.
Non-invasive screening methods are often recommended earlier for high-risk individuals. Imaging techniques like FibroScan (transient elastography) and Magnetic Resonance Elastography (MRE) accurately assess the amount of fat and the degree of scarring (fibrosis) in the liver. These tests help providers monitor the liver’s condition without requiring an invasive liver biopsy.
Genetic testing for the PNPLA3 and TM6SF2 variants is not yet standard practice for all MASLD patients. However, it is increasingly used in specialized clinics to refine risk stratification. Knowing a patient carries a high-risk variant encourages vigilance regarding adherence to metabolic health guidelines, making therapeutic lifestyle changes essential to prevent disease progression.