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Genetic risk for alcoholic liver disease: in vivo analysis of susceptibility genes

English title Genetic risk for alcoholic liver disease: in vivo analysis of susceptibility genes
Applicant Stickel Felix
Number 138747
Funding scheme Project funding
Research institution Hirslanden Bern AG Klinik Beau-Site
Institution of higher education University of Berne - BE
Main discipline Pathophysiology
Start/End 01.12.2011 - 31.03.2015
Approved amount 398'000.00
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All Disciplines (3)

Discipline
Pathophysiology
Clinical Pathophysiology
Internal Medicine

Keywords (5)

Alcoholic liver disease; Genetic risk; PNPLA3; Liver fibrosis; Functional genomics

Lay Summary (English)

Lead
Lay summary

Alcoholic liver disease (ALD) accounts for over fifty percent of all chronic liver diseases in industrialized countries and is responsible for > 25,000 deaths in 2005 in the United States alone. ALD comprises a spectrum of liver injury ranging from simple fatty liver to alcohol-induced liver scarring and, potentiall, cirrhosis. While literally all heavy drinkers have fatty liver, only a minority of 10-35% develop more severe let alone end-stage liver damage. Aggravation of ALD is modulated by environmental factors such as gender, obesity and chronic infection with hepatitis viruses. Twin studies suggest that up to 50% of the risk of cirrhosis in alcoholics is determined by inherited factors. The search for genetic factors that modulate the progression of ALD has resulted in abundant data from studies in humans of which the vast majority, however, remain unconfirmed. A highly topical finding constitutes the recent identification of a genetic variant in the gene coding for PNPLA3 as risk factors for severe ALD by several investigators including the principle applicant who found this to be true also in drinkers from central Europe.

In the present research project, the function and relevance of genetic variants found to associated with ALD shall be researched in mice in which the same genes have been inactivated artificially. Specifically, the function of two gene variants (patatin-like phospholipase domain-containing 3, PNPLA3 rs2073081; macrophage galactose-type C-type lectin 1, CLEC10A/MGL1; rs11654772) showing significant association with ALD in a recently performed genome-wide association study (GWAS) in 514 cases of alcoholic liver cirrhosis and 1,175 alcoholics without relevant liver injury is planned (pilot data leading to the project hypothesis). Emphasis will be put on the genes' effect on modulating the evolution of experimental liver scarring (fibrosis), fat accumulation and inflammation in these animals (AIM1). For this, mice with inactivated genes PNPLA3 and CLEC10A/MGL1 and normal control mice will be subjected to a recently developed animal model of alcoholic liver injury. To confirm the relevance of findings derived from animal experimentation, frozen human liver tissues shall be used to assess the tissue distribution and expression of the risk genes (AIM2). In addition, cultured cells (HuH-7) expressing normal or aberrant PNPLA3 will be treated with compunds that are known to mediate of ethanol totoxicity (acetaldehyde, hydrogen peroxide, hypoxia) to assess their impact on PNPLA3 expression and enzyme activity (AIM3). Finally, a possible association of the same genetic risk variants with progression of non-ALD chronic liver diseases (non-alcoholic fatty liver disease, NAFLD; chronic hepatitis C, CHC; hemochromatosis, HFE) will be tested by means of separate genetic case control studies (AIM4)

The research is structured as a Swiss single centre research endeavour but exploits data from an established Swiss/German/Austrian collaboration with access to unique patient collections, expertise and infrastructure required for systematic genetic detection, and further functional and clinical confirmation.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
DEPDC5 variants increase fibrosis progression in Europeans with chronic HCV infection
Burza Maria Antonella, Stickel Felix, Romeo Stefano (2016), DEPDC5 variants increase fibrosis progression in Europeans with chronic HCV infection, in Hepatology, 63(2), 418-427.
A two-stage genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as novel risk loci for alcohol-related cirrhosis
Buch Stefan, Stickel Felix, Trépo Eric, Hampe Jochen (2015), A two-stage genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as novel risk loci for alcohol-related cirrhosis, in Nature Genetics, 47(12), 1443-1448.
Transmembrane 6 superfamily member 2 gene E167K variant impacts on steatosis and liver damage in chronic hepatitis C patients
Milano Marta, Stickel Felix, Valenti Luca (2015), Transmembrane 6 superfamily member 2 gene E167K variant impacts on steatosis and liver damage in chronic hepatitis C patients, in Hepatology, 62(1), 111-117.
A common polymorphism in the NCAN gene is associated with hepatocellular carcinoma in alcoholic liver disease
Nischalke Hans, Stickel Felix, Spengler Ulrich (2014), A common polymorphism in the NCAN gene is associated with hepatocellular carcinoma in alcoholic liver disease, in Journal of Hepatology, 61(5), 1073-1079.
Evaluation of genome-wide loci of iron metabolism in hereditary hemochromatosis identifies PCSK7 as a predictor of liver cirrhosis
Stickel Felix, Buch Stefan (2014), Evaluation of genome-wide loci of iron metabolism in hereditary hemochromatosis identifies PCSK7 as a predictor of liver cirrhosis, in Human Molecular Genetics, 23(14), 3883-3890.
Genetics of alcoholic liver disease
Stickel Felix, Hampe Jochen (2012), Genetics of alcoholic liver disease, in Gut, 61(1), 150-159.

Collaboration

Group / person Country
Types of collaboration
Prof. Dr. Jean-Francois Dufour, Universitätsklinik für Viszerale Chirurgie und Medizin, Inselspital Switzerland (Europe)
- Exchange of personnel
Prof. Dr. Jochen Hampe, Universität Schleswig-Holstein, Campus Kiel Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Dr. Thomas Berg, Universität Leipzig Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Dr. Christian Datz, Universität Salzburg, Krankenhaus Oberndorf Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Associated projects

Number Title Start Funding scheme
169196 Systematic evaluation of the host genetics of alcohol-associated hepatocellular carcinoma 01.01.2017 Project funding
169196 Systematic evaluation of the host genetics of alcohol-associated hepatocellular carcinoma 01.01.2017 Project funding
117725 Liver fibrosis: targetting mTOR, ras and different G-proteins in man and rat 01.10.2007 Project funding

Abstract

Alcoholic liver disease (ALD) accounts for over fifty percent of all chronic liver diseases in industrialized countries and is responsible for > 25,000 deaths in 2005 in the United States alone. ALD comprises a spectrum of liver injury ranging from simple steatosis to alcohol-induced fibrosis and cirrhosis, either with or without inflammation. While many heavy drinkers have steatosis, only 10-35 % develop hepatic inflammation and 10-20% progress to cirrhosis. Progression of ALD is modulated by environmental factors such as gender, obesity and coinfection with chronic viral hepatitis. Twin studies suggested that up to 50% of the risk of cirrhosis in alcoholics is determined by genetic factors. The search for genetic factors that modulate the progression of ALD has resulted in abundant data from candidate gene case control studies of which the vast majority, however, remain unconfirmed in independent cohorts. A highly topical finding constitutes the recent identification of genetic variants in PNPLA3 as risk factors for advanced ALD in ethnically admixed Mestizo subjects. We have recently confirmed this for Caucasian alcoholics in a large candidate gene study and estimated the population attributable fraction at ~25% indicating that the remaining risk is governed by yet unidentified genetic factors.Herewith, a focused translational program of human disease susceptibility genes identified from a systematic genetic search for yet unknown susceptibility variants of ALD into suitable animal models shall be performed. Specifically, the functional analysis of two candidate genes (patatin-like phospholipase domain-containing 3, PNPLA3 rs2073081; macrophage galactose-type C-type lectin 1, MGL1; rs11654772) showing significant association with ALD in a recently performed genome-wide association study (GWAS) in 514 cases of alcoholic liver cirrhosis and 1,175 alcoholics without relevant liver injury is projected (pilot data leading to the project hypothesis). Emphasis will be put on their modulating effect on the evolution of experimental liver fibrosis, steatosis and necro-inflammation in vivo (AIM1). For this, PNPLA3 and MGL1 knock-out mice and wild-type littermates will be subjected to a recently developed animal model of alcoholic liver injury. To translate findings derived from animal experimentation, genotyped frozen human liver tissues shall be used to assess the tissue distribution and expression of the genes at the risk loci (AIM2). In addition, in vitro analysis of cells (HuH-7) expressing either wild-type or mutant PNPLA3 will be subjected to treatment with mediators of ethanol cytotoxicity (acetaldehyde, hydrogen peroxide, hypoxia) to assess their impact on PNPLA3 expression and hydrolase activity (AIM3). Finally, a possible association of genetic risk variants with progression of non-ALD chronic liver diseases (non-alcoholic fatty liver disease, NAFLD; chronic hepatitis C, CHC; hemochromatosis, HFE) will be tested by means of separate genetic case control studies (AIM4)The research is structured as a Swiss single centre research endeavour but exploits data from a Swiss/German/Austrian GWAS consortium with access to unique patient collections, expertise and infrastructure required for systematic genetic detection, in vivo/in vitro functional and clinical translation.
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