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PNPLA3 gene in liver diseases

  • Eric Trépo
    Correspondence
    Corresponding author. Address: Department of Gastroenterology, Hepatopancreatology, and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. Tel.: +32 2 555 51 31; fax: +32 2 555 48 02.
    Affiliations
    Inserm, UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d’Hématologie, Paris, France

    Department of Gastroenterology, Hepatopancreatology, and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium

    Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
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  • Stefano Romeo
    Affiliations
    Sahlgrenska Center for Cardiovascular and Metabolic Research, Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden

    Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden

    Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy
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  • Jessica Zucman-Rossi
    Affiliations
    Inserm, UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d’Hématologie, Paris, France

    Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France

    Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine, Bobigny, France

    Université Paris Diderot, Paris, France
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  • Pierre Nahon
    Affiliations
    Inserm, UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d’Hématologie, Paris, France

    Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine, Bobigny, France

    APHP, Service d’hépatologie, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France
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Published:March 30, 2016DOI:https://doi.org/10.1016/j.jhep.2016.03.011

      Summary

      Genome-wide association studies (GWAS) in the field of liver diseases have revealed previously unknown pathogenic loci and generated new biological hypotheses. In 2008, a GWAS performed in a population-based sample study, where hepatic liver fat content was measured by magnetic spectroscopy, showed a strong association between a variant (rs738409 C>G p.I148M) in the patatin-like phospholipase domain containing 3 (PNPLA3) gene and nonalcoholic fatty liver disease. Further replication studies have shown robust associations between PNPLA3 and steatosis, fibrosis/cirrhosis, and hepatocellular carcinoma on a background of metabolic, alcoholic, and viral insults. The PNPLA3 protein has lipase activity towards triglycerides in hepatocytes and retinyl esters in hepatic stellate cells. The I148M substitution leads to a loss of function promoting triglyceride accumulation in hepatocytes. Although PNPLA3 function has been extensively studied, the molecular mechanisms leading to hepatic fibrosis and carcinogenesis remain unclear. This unsuspected association has highlighted the fact that liver fat metabolism may have a major impact on the pathophysiology of liver diseases. Conversely, alone, this locus may have limited predictive value with regard to liver disease outcomes in clinical practice. Additional studies at the genome-wide level will be required to identify new variants associated with liver damage and cancer to explain a greater proportion of the heritability of these phenotypes. Thus, incorporating PNPLA3 and other genetic variants in combination with clinical data will allow for the development of tailored predictive models. This attractive approach should be evaluated in prospective cohorts.

      Abbreviations:

      GWAS (genome-wide association studies), CHC (chronic hepatitis C), SNP (single nucleotide polymorphism), HCV (hepatitis C virus), PNPLA3 (patatin-like phospholipase domain containing 3), NAFLD (nonalcoholic fatty liver disease), ALT (alanine aminotransferase), BMI (body mass index), HCC (hepatocellular carcinoma), NASH (nonalcoholic steatohepatitis), ALD (alcoholic liver disease), OR (odds ratio), HIV (human immunodeficiency virus), TG (triglycerides), WT (wild type), VLDL (very low density lipoproteins), MAF (minor allele frequency), NGS (next-generation sequencing), ROC (receiver operator characteristic), MZ (monozygotic), DZ (dizygotic), AUC (area under the curve)

      Keywords

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