PNPLA3, the history of an orphan gene of the potato tuber protein family that found an organ: The liver

T he patatin-like phospholipase domain containing 3 gene (PNPLA3) was an orphan gene looking for a disease until 2008 when the first genome-wide association study (GWAS) on nonalcoholic fatty liver disease (NAFLD) showed the association between the risk of liver fat accumulation and the nonsynonymous rs738409 C/G variant. Months later, the variant was significantly associated with NAFLD disease severity and alanine aminotransferase (ALT) levels, and the role of PNPLA3 as a modifier of the natural history of NAFLD was unequivocally replicated in different populations around the world, from children to adults. The enthusiasm about PNPLA3 led to the search for other biologically plausible liver disease associations, for instance, alcoholic liver disease (ALD) and an increased risk of steatosis in patients with chronic hepatitis C (CHC) and B. The variant was not only associated with cirrhosis and the occurrence of hepatocellular carcinoma (HCC), but the G allele was also identified as an independent risk factor for death and poor prognosis. At last, PNPLA3 found an organ: the liver. In this issue, Tr epo et al. explore the strength of the association between the rs738409 and the prevalence of HCC in cirrhosis patients by means of a meta-analysis of 2,503 individual participant data (IPD) from Europe. The authors found that the risk allele G was significantly associated with HCC (odds ratio [OR] per allele 5 1.77), after adjusting for sex, age, and obesity. Although the association was also found in patients with HCV-related cirrhosis (OR 5 1.55), in which the variant showed a small but statistically significant effect on the risk of HCC, the effect was more pronounced among patients with ALD (OR 5 2.20), suggesting that the variant influence is stronger, if not exclusive, on fat-derived HCC. Altogether, these results suggest some reflections: 1) rs738409 is the most consistent genetic modifier of the natural history of common chronic liver diseases in which inflammation and fibrogenesis are induced by environmental factors (dietary fat, alcohol, or viruses). 2) rs738409 is consistently associated with disease progression in liver diseases in which liver fat accumulation matters (NAFLD, ALD, and also CHC). Hence, instead of being “the cause” of the disease in terms of traditional monogenic disorders, the variant seems to be an important link between environmental stressors and the susceptibility of the liver to develop a more aggressive phenotype. 3) From a theoretical perspective, it can be argued that rs738409 has per se a substantial role in hepatocarcinogenesis because the variant is involved in related histological outcomes, such as steatosis and inflammation. Because the report of Tr epo et al. is a cross-sectional study, we cannot rule out the possibility that patients enrolled in this meta-analysis have had fatty liver prior to developing cirrhosis; thus, we do not know whether carriers of the G allele that developed HCC were those who had increased susceptibility to steatosis (in other terms, adjustment by steatosis). Considering that IPD is a unique opportunity to have full access to patients’ records, it would have been interesting to know whether the association between the variant and HCVHCC remained significant after adjusting for wellAbbreviations: ALD, alcoholic liver disease; ALT, alanine-aminotransferase; AUC, area under the curve; CHC, chronic hepatitis C; GWAS, genome-wide association study; HCC, hepatocellular carcinoma; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; PNPLA3, patatin-like phospholipase domain containing 3; ROC, receiver operating characteristic; SNP, single nucleotide polymorphism Received October 1, 2013; accepted October 10, 2013. Partially supported by grants PICT 2008-1521 and PICT 2010-0441 (Agencia Nacional de Promoci on Cient ıfica y Tecnol ogica), and UBACYT CM04 (Universidad de Buenos Aires). S.S. and C.J.P. belong to Consejo Nacional de Investigaciones Cient ıficas, y Tecnicas, (CONICET). Address reprint requests to: Silvia Sookoian, M.D., Ph.D., or Carlos J. Pirola, Ph.D., Instituto de Investigaciones M edicas A. Lanari-CONICET, Combatiente de Malvinas 3150, Buenos Aires (1427), Argentina. E-mail: sookoian.silvia@lanari.fmed. uba.ar or pirola.carlos@lanari.fmed. uba.ar; fax: 54-11-4523-8947. Copyright VC 2014 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI: 10.1002/hep.26895 Potential conflict of interest: Nothing to report.