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

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

Author information

1
Center for Chronically Sick Children, Charité - Universitätsmedizin Berlin, Berlin, Germany.
2
Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.
3
Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
4
Max Planck Institute for Molecular Genetics, Mass Spectrometry Facility, Berlin, Germany.
5
Institute for Biochemistry, Charité - Universitätsmedizin Berlin, Berlin, Germany.
6
Department of Pediatric Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
7
Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Abstract

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

PMID:
30444569
DOI:
10.1111/liv.14006

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