Genetic basis for NASH and ASH

1
Prevalence of histological diagnoses in
unselected drinkers
Normal (0-30)
Steatosis (60-100)
Steatohepatitis (20-30)
Fibrosis or cirrhosis (lt10)
2
Mechanisms of ALD
3
The candidate gene approach
Selection of Candidate Gene
Known / Characterised Polymorphisms
Search for Novel Polymorphisms
Disease Association Studies
Case - control
Family-based (TDT)
4
Candidate Genes in ALD

• Fatty liver genes
• Genes influencing oxidative stress
• Ethanol-metabolising enzymes
• Anti-oxidant enzymes (SODs/GSTs/GPxs)
• Endotoxin Rs/cytokines/cytokine Rs
• CD14 TLR4 / TNF?, IL-4, IL-10 /TNFR1, IL-Rs
• Genes influencing the immune response
• Cytokines/T cell regulatory molecules
• Other potential candidates
• Apoptosis/fibrosis

5
Only a minority of obese diabetics get NASH
Non-diabetic
Diabetic
Wanless et al Hepatology 1990 Erbey et al Am J
Med 2000
6
(No Transcript)
7
Candidate genes in NAFLD
8
Normal
Steatosis
CETP ApoE ?MTP
Steatohepatitis
CD14 TLR4 NOD2
?SOD2 ?TGF? ?AT
Fibrosis/ cirrhosis