UK Genetics of Liver Disease Consortium – ‘ UK GoLD ’
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UK Genetics of Liver Disease Consortium – ‘UK GoLD’
RepresentativesDr Quentin M. Anstee, Newcastle UniversityProf Alastair Burt, Newcastle UniversityProf Jeremy Lambert, Dundee University
1st MRC – IMPC Mouse Network Meeting, MRC Harwell, January 2012
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Background
• Liver disease is 5th most common cause of death in UK.
• Common liver diseases are result of the interaction between environmental factors and multiple genetic factors which determine susceptibility.
ONS, 2009
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UK GoLD
UK GoLD
In vivo models
Basic Science
DNA & Tissue Banks
Patient Cohorts
Clinical Trials
Industry Links
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Consortium Aims
To translate genetic association into a mechanistic understanding of disease pathogenesis and onwards
to the identification of novel therapeutic targets
• To identify genes that confer susceptibility to risk behaviors and determine disease severity;
• To understand mechanisms by which genes & gene-environment interactions cause disease;
• To validate GWAS and candidate gene associations through translational research;
• To identify and exploit novel potential therapeutic targets.
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Cross-Cutting Research Themes
• An initiator of liver disease risk
Mechanisms of Addiction Behavior
• Inflammation and hepatocellular injury
Mechanisms of Metabolic Liver Disease
• The final common pathway of liver injury
Modifiers of Hepatic Fibrosis and Liver Regeneration
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• An initiator of liver disease risk
Consortium Members
Mechanisms of Addiction Behavior
* Prof J. Lambert University of Dundee
* Dr D. Belelli University of Dundee
* Prof D. Stephens Sussex University
* Prof T. Smart UCL
Prof S. Brown MRC Harwell
*§ Dr Q.M. Anstee Newcastle University
*§ Prof H.C. Thomas Imperial College
§ Prof W. Wisden Imperial College
* MRC ‘GABA’ Addiction Cluster§ MRC ‘ICCAM’ Addiction Cluster
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ENU Mutagenesis: A Route to Gene Discovery
• ENU-induced mutations of GABRB1 gene leads to increased alcohol consumption, increased motivation for alcohol, and increased sensitivity to alcohol.
• Mutant mice show massive increases in tonic GABA currents in accumbens medium spiny neurones that are integral to reward and motivation, suggesting that decreasing tonic GABA currents may reduce alcohol intake
• In humans, allelic differences of the GABRB1 gene were associated with alcohol dependence.
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Linking Genes to Behaviour: Towards Endophenotypes
• Variations in the gene encoding a2 subunits of GABA receptors are associated with cocaine and alcohol addiction in people.
• Deleting a2 genes in mice reduces GABA currents in accumbens medium spiny neurones by 30% and prevents cocaine’s effects on conditioned behaviours.
WTa2-/-
0 3 100
100
200
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400
WTa2 deleted
Cocaine-facilitates conditioned reward in normal animals butnot if a2 subunits of GABA receptors are missing
Cocaine (mg/kg)
Con
ditio
ned
Rew
ard
a2bg2
Variations in the gene for a2 are associated with cocaine addiction in
peoplea4bd
Conditioned reinforcement in people
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• Inflammation and hepatocellular injury
Consortium Members
Mechanisms of Metabolic Liver Disease
* Dr Q.M. Anstee Newcastle University Prof A. Burt Newcastle University
* Prof C.P. Day Newcastle University * Prof A. Daly Newcastle University * Prof D. Jones Newcastle University * Prof R. Goldin Imperial College * Prof M. Thursz Imperial College * Prof S. Brown MRC Harwell * Prof R. Cox MRC Harwell * Dr P. Potter MRC Harwell
Prof D. Adams University of BirminghamDr P. Newsome University of Birmingham Dr G. Alexander Cambridge University
* MRC Harwell Liver ENU Research Programme
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Research Areas
• Non-Alcoholic Fatty Liver Disease– Progressive steatohepatitis and fibrosis associated with T2DM, obesity and
the metabolic syndrome. – Tissue oxidative stress response.– Role of caspase activation in disease pathogenesis.
• Immune Mediated Liver Injury– Primary Biliary Cirrhosis– Leucocyte-endothelial interactions and effector cell trafficking.
• Drug Induced Liver Disease & Toxicity– Idiosyncratic drug reactions– Paracetamol toxicity
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GWAS Activity
• ‘FLIP’ – Fatty Liver Inhibition of Progression– FP7 funded European research programme (Anstee, Burt, Daly, Day) – GWAS of biopsy-proven NAFLD– Establish large prospective and retrospective cohorts with NAFLD,
NASH and NAFLD-related HCC for translational study. • ‘UK PBC Consortium’
– Recently completed GWAS of PBC (Jones, Mells, Alexander)– Established the largest PBC cohort in the world for study.
• ‘GenomALC’ – Genetics of Alcoholic Liver Disease– International study, GWAS of ALD (Day)
• ‘DILIGEN’ - Drug Induced Liver Injury– GWAS of Idiosyncratic DILI across a range of agents (Daly, Day)
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• The final common pathway of liver injury
Consortium Members
Modifiers of Hepatic Fibrosis and Liver Regeneration
Prof A. Burt Newcastle University
Prof D. Mann Newcastle University Dr Q.M. Anstee Newcastle University
Prof M. Thursz Imperial College
Prof R. Goldin Imperial College
Dr P. Newsome University of BirminghamProf D. Adams University of Birmingham
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Translation from Association to Mechanism & Therapy
• Role of coagulation system activation in Liver fibrosis and stellate cell activation.
• Translational studies demonstrate that carriers of FvL mutation have accelerated fibrosis.
• This was confirmed in FvL mice and anticoagulation demonstrated to be an effected anti-fibrotic.
• On-going MRC Experimental medicine funded clinical trial (WAFT-C).
C57BL/6 FvL
H&E
Anti-
SMA
C57BL/6 + Warfarin
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Targeting the Renin-Angiotensin System (RAS) to Treat Fibrosis
• Hepatic stellate cells have a RAS that prevents apoptosis. Drugs that induce apoptosis will stimulate fibrosis reversion despite ongoing liver injury.
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UK GoLD Consortium Activity within the IMPC
• Current GWAS and hypothesis-driven research by UK GoLD members will help to guide IMPC gene prioritisation.
• UK GoLD members will establish a working group of clinicians to review IMPC clinical biochemistry data for metabolic, hepatitic and cholestatic compound phenotypes.
• Members will input into the phenotype pipelines to assess utility of screens and help guide technical development of the pipeline.
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UK GoLD Consortium Activity within the IMPC
• Members will integrate with IMPC to use mice in established basic research programmes as specific knockouts become available.
• Potential UK GoLD Secondary Screens include:– Electrophysiology (in vivo and in vitro), – Addiction/motivational behaviours, – Response to environmental challenges: EtOH, HFD, ALIOS, DILI,– Fibrosis models: MCD, CCl4, Thiocetamide, BDL, etc.
• UK GoLD will institute histological screens for liver disease in selected knockout animals. – Two internationally recognised expert liver pathologists (Burt and Goldin) with
extensive experience in murine histopathology.
• Bidirectional translational Studies.
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