Alcoholic liver disease (ALD) accounts for the majority of chronic
liver diseases in Western countries, and
alcoholic cirrhosis is among the premier causes of
liver failure,
hepatocellular carcinoma (HCC) and liver-related mortality causes. Studies in different genders and ethnic groups, as well as in twins provide strong evidence for a significant contribution of host genetic factors to
liver disease development in drinkers. The intense quest for genetic modifiers of alcohol-induced
fibrosis progression have identified and repeatedly confirmed a genetic polymorphism in the gene coding for patatin-like
phospholipase domain-containing 3 (PNPLA3;
adiponutrin; rs738409 C/G, M148I) as a risk factor for
alcoholic cirrhosis and its related complication, HCC, in different populations. Although carriership of one or both mutated PNPLA3 alleles does not explain the entire liver phenotypic variability in drinkers, it clearly represents one of the strongest single genetic modulators in a complex trait such as ALD. As more genetic data supporting its important role aggregates, novel insight as to PNPLA3's function and that of its genetic variation in liver injury is unveiled pointing to an important novel pathway in alcohol-mediated hepatic
lipid turnover with strong implications on
inflammation, extra cellular matrix remodelling, and hepatocarcinogenesis. Future study shall decipher whether the gathered knowledge can be translated into therapeutic benefits of patients.