Non-alcoholic fatty liver disease: a narrative review of genetics

Non-alcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver diseases worldwide. It encompasses a spectrum of disorders ranging from isolated hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. One of the key challenges in NAFLD is identifying which patients will progress. Epidemiological and genetic studies indicate a strong pattern of heritability that may explain some of the variability in NAFLD phenotype and risk of progression. To date, at least three common genetic variants in the PNPLA3, TM6SF2, and GCKR genes have been robustly linked to NAFLD in the population. The function of these genes revealed novel pathways implicated in both the development and progression of NAFLD. In addition, candidate genes previously implicated in NAFLD pathogenesis have also been identified as determinants or modulators of NAFLD phenotype including genes involved in hepatocellular lipid handling, insulin resistance, inflammation, and fibrogenesis. This article will review the current understanding of the genetics underpinning the development of hepatic steatosis and the progression of NASH. These newly acquired insights may transform our strategy to risk-stratify patients with NAFLD and to identify new potential therapeutic targets.