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

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

UK GoLD

UK GoLD

In vivo models

Basic Science

DNA & Tissue Banks

Patient Cohorts

Clinical Trials

Industry Links

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.

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

• 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

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.

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

300

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

• 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

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

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)

• 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

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

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.

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.

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.