1. UK Genetics of Liver Disease Consortium – ‘UK GoLD’
1st MRC – IMPC Mouse Network Meeting, MRC Harwell, January 2012
Representatives
Dr Quentin M. Anstee, Newcastle University
Prof Alastair Burt, Newcastle University
Prof Jeremy Lambert, Dundee University

2. 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

3. UK GoLD UK GoLD In vivo models Basic Science DNA & Tissue Banks
Patient Cohorts
Clinical Trials
Industry Links

4. Consortium Aims
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.
To translate genetic association into a mechanistic understanding of disease pathogenesis and onwards to the identification of novel therapeutic targets

5. 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

6. Consortium Members Mechanisms of Addiction Behavior
An initiator of liver disease risk
* Prof J. Lambert
Neuropharmacology
Dundee
* Dr D. Belelli
* Prof D. Stephens
Experimental Psychology
Sussex
* Prof T. Smart
UCL
Prof S. Brown
Genetics
MRC Harwell
*§ Dr Q.M. Anstee
Clinician Scientist
Newcastle
*§ Prof H.C. Thomas
Imperial
§ Prof W. Wisden
Molecular Neuroscience
* MRC ‘GABA’ Addiction Cluster
§ MRC ‘ICCAM’ Addiction Cluster

7. Consortium Members Mechanisms of Addiction Behavior
An initiator of liver disease risk
* Prof J. Lambert
University of Dundee
* Dr D. Belelli
* 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
* MRC ‘GABA’ Addiction Cluster
§ MRC ‘ICCAM’ Addiction Cluster

8. 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.

9. 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.
Variations in the gene for a2 are associated with cocaine addiction in people
a2bg2 WT
a2-/-
a4bd
Conditioned reinforcement in people

10. Consortium Members Mechanisms of Metabolic Liver Disease
Inflammation and hepatocellular injury
* Dr Q.M. Anstee
Newcastle University
Prof A. Burt
* Prof C.P. Day
* Prof A. Daly
* Prof D. Jones
* Prof R. Goldin
Imperial College
* Prof M. Thursz
* Prof S. Brown
MRC Harwell
* Prof R. Cox
* Dr P. Potter
Prof D. Adams
University of Birmingham
Dr P. Newsome
Dr G. Alexander
Cambridge University
* MRC Harwell Liver ENU Research Programme

11. 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

12. 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)

13. Consortium Members
Modifiers of Hepatic Fibrosis and Liver Regeneration
The final common pathway of liver injury
Prof A. Burt
Newcastle University
Prof D. Mann
Dr Q.M. Anstee
Prof M. Thursz
Imperial College
Prof R. Goldin
Dr P. Newsome
University of Birmingham
Prof D. Adams

14. 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

15. 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.

16. 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.
UK GoLD will institute secondary histological screens for liver disease in selected knockout animals.
Two internationally recognised expert liver pathologists (Burt and Goldin) with extensive experience in murine histopathology.
Members will input into the phenotype pipelines to assess utility of screens and help guide technical development of the pipeline.
Members will integrate with IMPC to use mice in established basic research programmes as specific knockouts become available.

17. 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.

18. 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.