Potential role of oxidative DNA damage in the impact of PNPLA3 variant (rs 738409 C&gt;G) in hepatocellular carcinoma risk
Authors: Stefano Romeo, Luca Valenti, Eric Trépo, Christophe Moreno, Pierre Nahon, Pierre Deltenre
Journal: Hepatology (2014)

The PNPLA3 rs738409 C>G variant encoding p.I148M is a risk factor for steatosis, inflammation, and cirrhosis.1, 2 In addition, in a meta-analysis of individual participant data, we showed that rs738409 is a robust genetic determinant of hepatocellular carcinoma (HCC) at the cirrhosis stage.3 To investigate mechanisms underpinning the association between rs738409 and HCC, Limagne et al. assessed plasma concentrations of oxidative stress (OS) surrogates, including a DNA damage marker, 8-hydroxy-deoxy-guanosine (8-OHdG), circulating oxidized fatty acids, and cholesterol levels in 43 CC and 43 GG patients with cirrhosis matched for demographics, cirrhosis severity, and time between cirrhosis diagnosis and inclusion. Despite a potential lack of power, the absence of a significant association between rs738409 and circulating oxidized lipids is not surprising. Indeed, under fasting conditions, lipids are carried in plasma mainly by lipoproteins, and specific depletion of monounsaturated oleic acid in GG homozygotes has been observed in circulating very-low-density lipoproteins,4 possibly the result of hepatic retention.5 Nevertheless, the researchers showed that GG homozygotes had higher levels of 8-OHdG. Although this finding should be replicated in independent cohorts, it suggests that GG homozygotes have heightened intracellular OS, possibly as a result of oxidation of intracellular lipid species. An alternative hypothesis could be failure of GG homozygotes to counteract OS during chronic inflammation. Overall, this may reflect increased DNA damage occurring in hepatocytes when the mutant PNPLA3 148M protein is highly expressed. The extent to which PNPLA3 variants also participate in complex genetic modulation of OS involved in alcohol-related hepatocarcinogenesis6 remains to be evaluated. The latter might be clarified if multigenic HCC risk models were developed using large, prospective cohorts of patients with cirrhosis. Stefano Romeo, M.D., Ph.D.1,2 Luca Valenti, M.D.3 Eric Trépo, M.D., Ph.D.4,5 Christophe Moreno, M.D., Ph.D.4,5 Pierre Nahon, M.D., Ph.D.6,7 Pierre Deltenre, M.D., Ph.D.4,8 1Department of Molecular and Clinical Medicine and Center for Cardiovascular and Metabolic Research Sahlgrenska Academy University of Gothenburg Gothenburg, Sweden 2Clinical Nutrition Unit Department of Medical and Surgical Sciences University Magna Graecia Catanzaro, Italy 3Department of Pathophysiology and Transplantation Università degli Studi di Milano, and Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico, Milan, Italy 4Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital Université Libre de Bruxelles Brussels, Belgium 5Laboratory of Experimental Gastroenterology Université Libre de Bruxelles Brussels, Belgium 6INSERM U773 Centre de Recherche Bichat Beaujon CRB3 University Paris 7 Paris, France 7Liver Unit Jean Verdier Hospital APHP University of Paris 13 Bondy, France 8Division of Gastroenterology and Hepatology Centre Hospitalier Universitaire Vaudois University of Lausanne Lausanne, Switzerland