Classification of IBD : the point of view of the geneticist.

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Classification of IBD the point of view of the
geneticist.

• Jean-Pierre Hugot
• Hopital Robert Debré
• jean-pierre.hugot_at_rdb.aphp.fr

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Functional candidate genes for IBD

• HLA Class II
• TNFa
• IL1/IL1ra
• ICAM-1
• Vitamine D Receptor
• CCR5
• CYP2D6
• MDR1
• TNFR1/TNFR2
• NOD1
• TLR4
• NFKB1
• PPARg
• Stromelysin 1
• CD14
• IL18

• IL2
• IL4
• IL10
• Interferon g
• Mucins
• hMLH1
• TCR
• Motilin
• TAP1/TAP2
• Complement
• TLR2
• PTPN22
• FOXP3

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TNFa polymorphisms
1. Biological significance demonstrated in
Human 2. Animal model of colitis TNFDARE 3.
Localisation at the IBD3 locus
Hampe J et al. Am J Hum Genet 1999
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MDR1 G2677T/A
Annese V et al. W J Gastroenterol
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MDR1 C3435T (synonymous)
Annese V et al. W J Gastroenterol
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TLR4 Asp299Gly
Vermeire S et al. Gut 2004
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NOD1 32656
McGovern D. et al. Hum Mol Genet 2005
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MYO9B Ala1011Ser
OR1.19 95 confidence interval 1.11-1.28
Van Bodegraven AA et al. Gastroenterology in press
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TNFa
NOD1
B DEFENSIN 2
TLR4
MDR1
MYO9B
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Positional candidate genes

• CARD15/NOD2
• OCTN1/2
• DLG5
• TNFS15
• IL23R
• APG16L1

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Rioux J. et al. Nature Genet 2001
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DLG5

• Is a gene located on chromosome band 10q23
• Several variants have been found
• One frequent (34 of the control chromosomes)
• One rare (lt1 of the control chromosomes)
• Few private variations
• There are statistically associated with Crohn
  Disease and IBD in general.
• They code for non conservative variations of the
  protein (R10Q et P1371Q).
• Dlg5 is a PDZ protein potentially involved in
  maintenance of the epithelial structure .

M Stoll et al. Nature Genet 2004
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TNFS15
Yamazaki et al. Hum Mol Genet 2005
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IL23R Arg 381 Gln
Duerr RH et al. Science 2006
rs11209026 (Arg381Gln) CD 0.025 Controls 0.07.
OR 0.34
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ATG16L1

• Located on chromosome 2.
• Homologous to a yeast gene involved in
  autophagia.
• A non conservative variation is associated with
  CD but not UC.
• Synergistic effect with CARD15/NOD2.

Hampe J et al. Nature Genet 2007
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NOD1
IL23R
B DEFENSIN 2
ATG16L1
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The point of view of the geneticist How to
rely the genotype with the phenotype?
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A mendelian disorder?
PHENOTYPE
GENOTYPE
Phenotype 1
Génotype 1
Phenotype 2
Génotype 2
Phenotype 3
Génotype 3
Phenotype 4
Génotype 4
Phenotype 5
Génotype 5
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There is a significant concordance for the
sub-phenotype of affected relatives.Gastroenterol
ogy 1996 111(3)
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Relationship between a genotype and a subphenotype

• CARD15 ileal CD, complicated disease, young
  AOO.
• OCTN1/2 iléal CD?, UC?
• DLG5 CD, UC?, no subphenotype
• NOD1 CD, young AOO, no subphenotype
• ATG16L1 CD, no subphenotype
• IL23R CD, no subphenotype
• TNFS15 IBD
• Etc..

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The relationship between the genotype and the
phenotype is complex
Phenotype 1
G1G2E1
Phenotype 2
G1G3E2
Phenotype 3
G2G4E1
Phenotype 4
G3G5E3
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G
E
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If we make the hypothesis that a disease is
defined by the loss of a biological function.
Mendelian disorder
Example oxygene transport/congenital anemia
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Complex genetic disorders
X
X
X
X
X
X
X
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Complex genetic disorders are the result of the
regulation of a network of biological functions
F2
F1
F3
F1
F4
F1
F3
Victor JM, Lesne A et al. In preparation
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Age incidence of CD
Victor JM, Lesne A et al. In preparation
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Victor JM, Lesne A et al. In preparation
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POURCENTAGE D'AGREGATIONS FAMILIALES DE MC
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The relationship between the genotype and the
phenotype is complex
Phenotype 1
G1G2E1
Phenotype 2
G1G3E2
Phenotype 3
G2G4E1
Phenotype 4
G3G5E3
Is it enough?
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Monozygotic twins are 20-50 concordant
This suggests additional stochastic events
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In complex genetic disorders, the concept of
causality is weak.Even with a complete
knowledge of the causative factors, genetic
counseling will remain difficult.