Genetic modulators of metabolic dysfunction-associated steatotic liver disease (MASLD) and their epistatic interactions: from in vitro and animal models to clinical outcomes.
Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as NAFLD (non-alcoholic fatty liver disease), is a growing global concern, affecting nearly a third of the world’s population. This umbrella term covers a range of liver pathologies, from reversible disease stages like simple steatosis, to irreversible conditions such as cirrhosis and hepatocellular carcinoma (HCC). MASLD, which may result from metabolic risk factors like obesity and type 2 diabetes, is projected to increase due to a rise in sedentary lifestyles. This review addresses genetic influences that predispose to disease development, including the role of risk-conferring and protective/preventive alleles. The epistatic relationships between genetic variants can significantly influence the development and progression of MASLD. Key genetic variants, such as those located in the PNPLA3, TM6SF2, and MBOAT7 genes, often interact to exacerbate MASLD severity and play key roles in lipid metabolism and liver inflammation. For example, the co-expression of certain PNPLA3 and TM6SF2 variants increases the risk of advanced fibrosis and HCC. Some variants located in HSD17B13 and MTARC1 offer protective effects, reducing the risk of severe liver disease despite comorbidities such as obesity, and can mitigate the harmful effects of these risk alleles. Additionally, the potential of polygenic risk scores (PRS) to predict MASLD development and its complications is also discussed, although challenges remain, particularly in underrepresented populations due to the lack of comprehensive catalogues of genetic variation. Understanding these complex gene-gene interactions and the role of the environment underscores the importance of considering epistatic relationships when assessing MASLD risk and developing personalized therapeutic strategies, which could ease the future burden on healthcare systems. · Metabolic dysfunction-associated steatotic liver disease (MASLD) affects nearly one-third of the global population, with rising incidence due to sedentary lifestyles, obesity, and type 2 diabetes. · It is estimated that nearly 50% of MASLD patients have heritable predisposition genetic variants in genes such as PNPLA3 and TM6SF2, which play significant roles in MASLD development. · Several protective alleles have also been identified, which may mitigate MASLD progression despite genetic variants and environmental risk factors. · Epistatic relationship between predisposing and protective genes can influence Polygenic Risk Score and improve the precision detection and early diagnosis of liver metabolic diseases. · Risk-modifying variants have different allelic frequencies according to the population considered.
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