Genetic determinants of steatosis and fibrosis progression in paediatric non-alcoholic fatty liver disease

Liver Int. 2019 Mar;39(3):540-556. doi: 10.1111/liv.14006. Epub 2018 Dec 21.


Background and aims: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and adolescents today. In comparison with adult disease, paediatric NAFLD may show a periportal localization, which is associated with advanced fibrosis. This study aimed to assess the role of genetic risk variants for histological disease pattern and severity in childhood NAFLD.

Methods: We studied 14 single nucleotide polymorphisms (SNP) in a cohort of 70 adolescents with biopsy-proven NAFLD. Genotype was compared to an adult control cohort (n = 200) and analysed in relation to histological disease severity and liver tissue proteomics.

Results: Three of the 14 SNPs were significantly associated with paediatric NAFLD after FDR adjustment, rs738409 (PNPLA3, P = 2.80 × 10-06 ), rs1044498 (ENPP1, P = 0.0091) and rs780094 (GCKR, P = 0.0281). The severity of steatosis was critically associated with rs738409 (OR=3.25; 95% CI: 1.72-6.52, FDR-adjusted P = 0.0070). The strongest variants associated with severity of fibrosis were rs1260326, rs780094 (both GCKR) and rs659366 (UCP2). PNPLA3 was associated with a portal pattern of steatosis, inflammation and fibrosis. Proteome profiling revealed decreasing levels of GCKR protein with increasing carriage of the rs1260326/rs780094 minor alleles and downregulation of the retinol pathway in rs738409 G/G carriers. Computational metabolic modelling highlighted functional relevance of PNPLA3, GCKR and UCP2 for NAFLD development.

Conclusions: This study provides evidence for the role of PNPLA3 as a determinant of portal NAFLD localization and severity of portal fibrosis in children and adolescents, the risk variant being associated with an impaired hepatic retinol metabolism.

Keywords: genetics; metabolic modelling; paediatric NAFLD; proteomics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adolescent
  • Age Factors
  • Case-Control Studies
  • Child
  • Disease Progression
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Lipase / genetics*
  • Liver / enzymology
  • Liver Cirrhosis / diagnosis
  • Liver Cirrhosis / enzymology
  • Liver Cirrhosis / genetics*
  • Male
  • Membrane Proteins / genetics*
  • Non-alcoholic Fatty Liver Disease / diagnosis
  • Non-alcoholic Fatty Liver Disease / enzymology
  • Non-alcoholic Fatty Liver Disease / genetics*
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Risk Assessment
  • Risk Factors
  • Severity of Illness Index
  • Time Factors
  • Uncoupling Protein 1 / genetics*
  • Vitamin A / metabolism


  • Adaptor Proteins, Signal Transducing
  • GCKR protein, human
  • Membrane Proteins
  • UCP1 protein, human
  • Uncoupling Protein 1
  • Vitamin A
  • Lipase
  • adiponutrin, human