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Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: Evidence from a meta-analysis of individual participant data

Authors

  • Eric Trépo,

    1. Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
    2. Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
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  • Pierre Nahon,

    1. INSERM U773, Centre de Recherche Bichat Beaujon CRB3, University Paris 7, Paris, France
    2. Liver Unit, Jean Verdier Hospital, APHP, University of Paris 13, Bondy, France
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  • Gianluca Bontempi,

    1. Machine Learning Group, Department of Computer Science, Université Libre de Bruxelles, Brussels, Belgium
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  • Luca Valenti,

    1. Department of Pathophysiology and Transplantation, Università degli Studi di Milano, and Internal Medicine, Milan, Italy
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  • Edmondo Falleti,

    1. Department of Medical Sciences Experimental and Clinical, Medical Liver Transplantation Unit, University of Udine, Udine, Italy
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  • Hans-Dieter Nischalke,

    1. Department of Internal Medicine I, University of Bonn, Bonn, Germany
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  • Samia Hamza,

    1. Service d'Hépato-gastroentérologie, Dijon, France
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  • Stefano Ginanni Corradini,

    1. Department of Clinical Medicine Sapienza, University of Rome, Italy
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  • Maria Antonella Burza,

    1. Department of Molecular and Clinical Medicine and Center for Cardiovascular and Metabolic Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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  • Erwan Guyot,

    1. University Paris 13-UFR SMBH/INSERM U698, Bobigny, France
    2. Biochemistry Unit, Jean Verdier Hospital, APHP, University Paris 13, Bondy, France
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  • Benedetta Donati,

    1. Department of Pathophysiology and Transplantation, Università degli Studi di Milano, and Internal Medicine, Milan, Italy
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  • Ulrich Spengler,

    1. Department of Internal Medicine I, University of Bonn, Bonn, Germany
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  • Patrick Hillon,

    1. Service d'Hépato-gastroentérologie, Dijon, France
    2. INSERM U866, University of Burgundy, Dijon, France
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  • Pierluigi Toniutto,

    1. Department of Medical Sciences Experimental and Clinical, Medical Liver Transplantation Unit, University of Udine, Udine, Italy
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  • Jean Henrion,

    1. Service d'Hépato-Gastroentérologie, Hôpital de Jolimont, Haine-Saint-Paul, Belgium
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  • Denis Franchimont,

    1. Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
    2. Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
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  • Jacques Devière,

    1. Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
    2. Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
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  • Philippe Mathurin,

    1. Service d'Hépato-Gastroentérologie, Hôpital Huriez, Lille, France
    2. INSERM U995, Universite Lille Nord de France, Lille, France
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  • Christophe Moreno,

    1. Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
    2. Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
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  • Stefano Romeo,

    1. Department of Molecular and Clinical Medicine and Center for Cardiovascular and Metabolic Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
    2. Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy
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  • Pierre Deltenre

    Corresponding author
    1. Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
    2. Service d'Hépato-Gastroentérologie, Hôpital de Jolimont, Haine-Saint-Paul, Belgium
    3. Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
    • Address reprint requests to: Pierre Deltenre, M.D., Ph.D., Service d'Hépato-Gastroentérologie, Hôpital de Jolimont, 159 rue Ferrer, 7100 Haine-Saint-Paul, Belgium. E-mail: pierre.deltenre@skynet.be; fax: +32 64 233180.

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  • See Editorial on Page 2068

  • Potential conflict of interest: Nothing to report.

  • The Belgian “National Fund for Scientific Research” (FNRS) supported this work. E.T. is a postdoctoral researcher of the FNRS.

  • This study has been selected for oral presentation during The Liver Meeting for the 64th Annual Meeting of the American Association for the Study of Liver Diseases.

Abstract

The incidence of hepatocellular carcinoma (HCC) is increasing in Western countries. Although several clinical factors have been identified, many individuals never develop HCC, suggesting a genetic susceptibility. However, to date, only a few single-nucleotide polymorphisms have been reproducibly shown to be linked to HCC onset. A variant (rs738409 C>G, encoding for p.I148M) in the PNPLA3 gene is associated with liver damage in chronic liver diseases. Interestingly, several studies have reported that the minor rs738409[G] allele is more represented in HCC cases in chronic hepatitis C (CHC) and alcoholic liver disease (ALD). However, a significant association with HCC related to CHC has not been consistently observed, and the strength of the association between rs738409 and HCC remains unclear. We performed a meta-analysis of individual participant data including 2,503 European patients with cirrhosis to assess the association between rs738409 and HCC, particularly in ALD and CHC. We found that rs738409 was strongly associated with overall HCC (odds ratio [OR] per G allele, additive model = 1.77; 95% confidence interval [CI]: 1.42-2.19; P = 2.78 × 10−7). This association was more pronounced in ALD (OR = 2.20; 95% CI: 1.80-2.67; P = 4.71 × 10−15) than in CHC patients (OR = 1.55; 95% CI: 1.03-2.34; P = 3.52 × 10−2). After adjustment for age, sex, and body mass index, the variant remained strongly associated with HCC. Conclusion: Overall, these results suggest that rs738409 exerts a marked influence on hepatocarcinogenesis in patients with cirrhosis of European descent and provide a strong argument for performing further mechanistic studies to better understand the role of PNPLA3 in HCC development. (Hepatology 2014;59:2170–2177)

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