PNPLA3 I148M variant and hepatocellular carcinoma: A common genetic variant for a rare disease

Hepatocellular carcinoma (HCC) is highly associated with chronic liver disease. The rs738409 genetic variant in the patatin-like phospholipase domain-containing 3 (PNPLA3, adiponutrin) gene has been implicated as a genetic determinant of the entire spectrum of liver diseases, ranging from steatosis, chronic hepatitis, cirrhosis and ultimately to HCC. In this review, first we will examine the current genetic theories of disease susceptibility. Next, we will analyze the evidences for the association between PNPLA3 I148M variant and HCC. Moreover, we will exploit this association to propose a new paradigm in human genetics: a common genetic variant contributing to a rare disease. Finally, we will examine the molecular genetics of PNPLA3 and, specifically, the theories that have been proposed to explain the function of PNPLA3 in health and disease. © 2012 Editrice Gastroenterologica Italiana S.r.l.