Digestive Diseases

Hepatology 2016 - The Panorama

Genetic Discoveries Highlight Environmental Factors as Key Drivers of Liver Disease

Chung B.K.a,b,d · Karlsen T.H.b-f

Author affiliations

aCentre for Liver Research and National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit, College of Medical and Dental Sciences, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; bNorwegian PSC Research Center, and cSection of Gastroenterology, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, dInstitute of Clinical Medicine, Faculty of Medicine, University of Oslo, eResearch Institute of Internal Medicine, Division of Cancer Medicine, Inflammatory Medicine and Transplantation, Oslo University Hospital, and fK.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway

Keywords: PhenylketonuriaTyrosinemiaCystic fibrosisDrug-induced liver injuryAutoimmune hepatitisPrimary biliary cholangitisPrimary sclerosing cholangitis

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Dig Dis 2017;35:323-333
https://doi.org/10.1159/000456583

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Article / Publication Details

First-Page Preview
Abstract of Hepatology 2016 - The Panorama

Published online: May 03, 2017
Issue release date: May 2017

Number of Print Pages: 11
Number of Figures: 2
Number of Tables: 2

ISSN: 0257-2753 (Print)
eISSN: 1421-9875 (Online)

For additional information: https://www.karger.com/DDI

Abstract

Background: Over the last 50 years, genetic studies have uncovered a spectrum of rare and common alleles that confer susceptibility to both Mendelian and complex forms of liver disease. For disorders of Mendelian inheritance, identification of the causal variants has demonstrated that common environmental exposures can elicit severe liver pathogenesis in predisposed individuals. Specific environmental triggers for complex liver disorders are largely unknown; however, large-scale association studies indicate that environmental triggers are the predominant factors in driving liver pathophysiology. Key Messages: In Mendelian liver disorders, a single rare variant of major effect is often responsible for disease development. Gene-sequencing technologies have greatly facilitated the discovery of causal variants for Mendelian diseases and are increasingly utilized in molecular and clinical genetics for diagnostic and counselling purposes. By contrast, genetic susceptibility for complex liver disorders is heterogeneous, as many different genes acting on multiple distinct pathways influence disease onset and severity. Risk variants for complex liver disorders are relatively common, typically of small effect size and detected by genome-wide association studies (GWAS), which compare the genetic variation of specific loci using thousands of patients and healthy controls. Thus far, GWAS have detected dozens of unique and overlapping risk alleles for complex liver disease, but these account for less than a quarter of the overall disease liability. These observations emphasize that environmental exposures on a background of genetic predisposition are significant drivers of liver pathophysiology. Rare variants of large effect size, undetectable by GWAS, may also affect the development of complex disease on a case-to-case basis but evidence for such a scenario remains to be determined. Conclusions: Genetic technologies have identified numerous risk genes for Mendelian and complex liver disorders transforming disease recognition. For complex liver disorders, deciphering the interplay between genetic risk and environment determinants remains a significant challenge for unlocking the development of novel and personalized interventions.

© 2017 S. Karger AG, Basel



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Article / Publication Details

First-Page Preview
Abstract of Hepatology 2016 - The Panorama

Published online: May 03, 2017
Issue release date: May 2017

Number of Print Pages: 11
Number of Figures: 2
Number of Tables: 2

ISSN: 0257-2753 (Print)
eISSN: 1421-9875 (Online)

For additional information: https://www.karger.com/DDI

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