I148M patatin-like phospholipase domain-containing 3 gene variant and severity of pediatric nonalcoholic fatty liver disease

Authors

  • Luca Valenti,

    1. Department of Internal Medicine, Università degli Studi, Ospedale Maggiore Policlinico (Ca' Granda) Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
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  • Anna Alisi,

    1. Liver Unit, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy
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  • Enrico Galmozzi,

    1. Department of Internal Medicine, Università degli Studi, Ospedale Maggiore Policlinico (Ca' Granda) Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
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  • Andrea Bartuli,

    1. Rare Diseases Unit, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy
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  • Benedetta Del Menico,

    1. Department of Internal Medicine, Università degli Studi, Ospedale Maggiore Policlinico (Ca' Granda) Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
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  • Arianna Alterio,

    1. Liver Unit, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy
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  • Paola Dongiovanni,

    1. Department of Internal Medicine, Università degli Studi, Ospedale Maggiore Policlinico (Ca' Granda) Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
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  • Silvia Fargion,

    Corresponding author
    1. Department of Internal Medicine, Università degli Studi, Ospedale Maggiore Policlinico (Ca' Granda) Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
    • Center for Metabolic Diseases of the Liver, Department of Internal Medicine, Università degli Studi, Ospedale Maggiore Policlinico (Ca' Granda) Istituto di Ricovero e Cura a Carattere Scientifico, Via F. Sforza 35, Milan, Italy 20122
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    • Fax: 390250320296

  • Valerio Nobili

    1. Liver Unit, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy
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  • Potential conflict of interest: Nothing to report.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in children. Genetic variability, which is a main player in NAFLD, is especially characterized by polymorphisms in genes involved in the development and progression of the disease to nonalcoholic steatohepatitis (NASH). Recently, the rs738409 C>G adiponutrin/patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphism, which encodes the I148M protein variant in the catalytic domain, has been associated with severe steatosis, NASH, and liver fibrosis in adults. In this study, we investigated the association between the rs738409 PNPLA3 gene polymorphism and NAFLD in 149 consecutive children and adolescents (age = 6-13 years) with biopsy-proven NAFLD. We analyzed the rs738409 polymorphism by a 5′-nuclease TaqMan assay and assessed its association with NASH: 41% of the subjects with NAFLD showed heterozygosity and 15% showed homozygosity for the at-risk G allele. The rs738409 genotype did not influence the body mass, adiposity, lipid levels, or insulin resistance and was not associated with alanine aminotransferase levels. Interestingly, the rs738409 G allele was strongly associated with the severity of steatosis (P < 0.0001), the presence of NASH (P < 0.0001), hepatocellular ballooning (P < 0.0001), lobular inflammation (P < 0.0001), and the presence of fibrosis (P = 0.01) independently of confounders. Individuals carrying two minor G alleles almost always had severe steatosis and NASH, heterozygotes were at intermediate risk, and patients negative for G alleles had milder and often uncomplicated steatosis. Conclusion: The PNPLA3 rs738409 polymorphism is associated with steatosis severity, hepatocellular ballooning, lobular inflammation, and perivenular fibrosis in pediatric NAFLD. (HEPATOLOGY 2010)

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