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

Hudert, C. A., Selinski, S., Rudolph, B., Bläker, H., Loddenkemper, C., Thielhorn, R., et al. (2019). Genetic determinants of steatosis and fibrosis progression in paediatric non‐alcoholic fatty liver disease. Liver International, 39(3), 540-556. doi:10.1111/liv.14006.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0002-E201-D Version Permalink: http://hdl.handle.net/21.11116/0000-0003-554D-8
Genre: Journal Article

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© 2018 John Wiley & Sons A/S.
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 Creators:
Hudert, Christian A., Author
Selinski, Silvia , Author
Rudolph, Birgit, Author
Bläker, Hendrik , Author
Loddenkemper, Christoph, Author
Thielhorn, Ria1, Author              
Berndt, Nikolaus, Author
Golka, Klaus, Author
Cadenas, Cristina , Author
Reinders, Jörg , Author
Henning, Stephan, Author
Bufler, Philip, Author
Jansen, Peter L. M., Author
Holzhütter, Hermann‐Georg , Author
Meierhofer, David1, Author              
Hengstler, Jan G., Author
Wiegand, Susanna , Author
Affiliations:
1Mass Spectrometry (Head: David Meierhofer), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479669              

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Free keywords: genetics; metabolic modelling; paediatric NAFLD; proteomics
 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.

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Language(s): eng - English
 Dates: 2018-11-052018-11-162019-03
 Publication Status: Published in print
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 Identifiers: DOI: 10.1111/liv.14006
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Title: Liver International
Source Genre: Journal
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Pages: 17 Volume / Issue: 39 (3) Sequence Number: - Start / End Page: 540 - 556 Identifier: -