Volume 39, Issue 3 pp. 540-556

METABOLIC LIVER DISEASE

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

Christian A. Hudert,

Corresponding Author

Christian A. Hudert

[email protected]

orcid.org/0000-0002-3642-0838

Center for Chronically Sick Children, Charité – Universitätsmedizin Berlin, Berlin, Germany

Correspondence

Christian A. Hudert, Center for Chronically Sick Children, Charité – Universitätsmedizin Berlin, Berlin, Germany.

Email: [email protected]

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Silvia Selinski,

Silvia Selinski

Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany

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Birgit Rudolph,

Birgit Rudolph

Institute of Pathology, Charité – Universitätsmedizin Berlin, Berlin, Germany

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Hendrik Bläker,

Hendrik Bläker

Institute of Pathology, Charité – Universitätsmedizin Berlin, Berlin, Germany

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Christoph Loddenkemper,

Christoph Loddenkemper

Institute of Pathology, Charité – Universitätsmedizin Berlin, Berlin, Germany

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Ria Thielhorn,

Ria Thielhorn

Max Planck Institute for Molecular Genetics, Mass Spectrometry Facility, Berlin, Germany

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Nikolaus Berndt,

Nikolaus Berndt

Institute for Biochemistry, Charité – Universitätsmedizin Berlin, Berlin, Germany

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Klaus Golka,

Klaus Golka

Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany

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Cristina Cadenas,

Cristina Cadenas

Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany

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Jörg Reinders,

Jörg Reinders

Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany

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Stephan Henning,

Stephan Henning

Department of Pediatric Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, Germany

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Philip Bufler,

Philip Bufler

Department of Pediatric Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, Germany

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Peter L. M. Jansen,

Peter L. M. Jansen

Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

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Hermann-Georg Holzhütter,

Hermann-Georg Holzhütter

Institute for Biochemistry, Charité – Universitätsmedizin Berlin, Berlin, Germany

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David Meierhofer,

David Meierhofer

Max Planck Institute for Molecular Genetics, Mass Spectrometry Facility, Berlin, Germany

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Jan G. Hengstler,

Jan G. Hengstler

Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany

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Susanna Wiegand,

Susanna Wiegand

Center for Chronically Sick Children, Charité – Universitätsmedizin Berlin, Berlin, Germany

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Christian A. Hudert,

Corresponding Author

Christian A. Hudert

[email protected]

orcid.org/0000-0002-3642-0838

Center for Chronically Sick Children, Charité – Universitätsmedizin Berlin, Berlin, Germany

Correspondence

Christian A. Hudert, Center for Chronically Sick Children, Charité – Universitätsmedizin Berlin, Berlin, Germany.

Email: [email protected]

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Silvia Selinski,

Silvia Selinski

Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany

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Birgit Rudolph,

Birgit Rudolph

Institute of Pathology, Charité – Universitätsmedizin Berlin, Berlin, Germany

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Hendrik Bläker,

Hendrik Bläker

Institute of Pathology, Charité – Universitätsmedizin Berlin, Berlin, Germany

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Christoph Loddenkemper,

Christoph Loddenkemper

Institute of Pathology, Charité – Universitätsmedizin Berlin, Berlin, Germany

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Ria Thielhorn,

Ria Thielhorn

Max Planck Institute for Molecular Genetics, Mass Spectrometry Facility, Berlin, Germany

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Nikolaus Berndt,

Nikolaus Berndt

Institute for Biochemistry, Charité – Universitätsmedizin Berlin, Berlin, Germany

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Klaus Golka,

Klaus Golka

Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany

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Cristina Cadenas,

Cristina Cadenas

Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany

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Jörg Reinders,

Jörg Reinders

Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany

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Stephan Henning,

Stephan Henning

Department of Pediatric Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, Germany

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Philip Bufler,

Philip Bufler

Department of Pediatric Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, Germany

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Peter L. M. Jansen,

Peter L. M. Jansen

Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

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Hermann-Georg Holzhütter,

Hermann-Georg Holzhütter

Institute for Biochemistry, Charité – Universitätsmedizin Berlin, Berlin, Germany

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David Meierhofer,

David Meierhofer

Max Planck Institute for Molecular Genetics, Mass Spectrometry Facility, Berlin, Germany

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Jan G. Hengstler,

Jan G. Hengstler

Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany

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Susanna Wiegand,

Susanna Wiegand

Center for Chronically Sick Children, Charité – Universitätsmedizin Berlin, Berlin, Germany

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First published: 16 November 2018

https://doi.org/10.1111/liv.14006

Citations: 46

Hengstler and Wiegand contributed equally.

Funding information

This work was supported by the German Federal Ministry of Education and Research (BMBF, Liver Systems Medicine—LiSyM, FKZ 031L0057, 031L0058).

Handling Editor: Frank Tacke

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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.

CONFLICT OF INTEREST

All authors declare no competing interests and have approved the final article.

Supporting Information

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Citing Literature

Volume39, Issue3

March 2019

Pages 540-556

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

Abstract

Background and Aims

Methods

Results

Conclusions

CONFLICT OF INTEREST

Supporting Information

REFERENCES

Citing Literature

References

Information

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

Abstract

Background and Aims

Methods

Results

Conclusions

CONFLICT OF INTEREST

Supporting Information

REFERENCES

Citing Literature

References

Related

Information