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The Genetics of IBD

Controversies in IBD November 12th 2011

Mark Seielstad, Ph.D.

Institute for Human Genetics University of California San Francisco

Is IBD Genetic?

Crohn’s UC

35% MZ twins concordant 16% of MZ twins concordant

3% of DZ twins concordant 2% of DZ twins concordant

•  Excess concordance of identical twins indicates the existence of “causal” genetic variation

•  Less than total concordance for MZ twins suggests polygenic inheritance and indicates role of environment – the definition of a “complex disease”

•  Higher concordances for Crohn’s probably bespeak a more “genetic” basis for this form of disease

Can we find genes related to IBD?

Chris Cotsapas & Mark Daly

How do we find genes for IBD? (effects are often subtle, requiring large samples)

Patients/Cases Healthy/Controls

PTPN22 – 620 TRP: 28% PTPN22 – 620 TRP: 17% PTPN22 – 620 ARG: 72% PTPN22 – 620 ARG: 83%

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BeadChip

Norm Theta A Infinium I

Allele-Specific Primer Extension

Infinium II Single Base Extension

B

71 Genes for Crohn’s; 28 shared with UC (misdiagnoses?)

(22,000 cases : 29,000 controls)

>47 Genes for UC; ~99 unique genes for IBD (16,000 cases : 32,000 controls) (fewer genes for UC, consistent with twin

studies) What new insights have genetic results provided?

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Multiple Genes in Pathways are Associated

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Highly Simplified Scheme for Signaling by T-Cell Receptors, Emphasizing the Proximal Events in Signal Transduction.

Cho JH, Gregersen PK. N Engl J Med 2011;365:1612-1623

Current Concepts Concerning the Pathogenesis of Ulcerative Colitis.

Danese S, Fiocchi C. N Engl J Med 2011;365:1713-1725

Many Associations shared other Autoimmunities

Is IBD an Autoimmune (cellular immune response to self antigens) or an

Inflammatory Disease?

•  Strong HLA associations are a hallmark of autoimmune disease – and presentation of self-antigens by HLA to T-cells is a prerequisite

•  Crohn’s has weak/no HLA association – and few/no autoantibodies

•  UC has strong/typical HLA associate – and pANCA and Tropomyosin 5 as possible autoantigens

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Why might variants that increase disease risk be common?

Genetic Associations of Autoimmune Diseases along the Interleukin-12 and Interleukin-23 Signaling Pathways.

Cho JH, Gregersen PK. N Engl J Med 2011;365:1612-1623

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Is any of this useful?

What next?

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Annual  Reviews  

Utility of Results

Where is the Missing Heritability Possible Explanations

1.  “hundreds” of additional low-impact variants remain to be found

2.  Causal variants haven’t been identified 3.  Heritability has been poorly estimated 4.  GxG and GxE interactions 5.  Classes of variation (e.g., CNV) remain

hidden 6.  Low frequency variants of larger effect

size remain to be found

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Possible Explanations

1.  “hundreds” of additional low-impact variants remain to be found

2.  Causal variants haven’t been identified 3.  Heritability has been poorly estimated 4.  GxG and GxE interactions 5.  Classes of variation (e.g., CNV) remain

hidden 6.  Low frequency variants of larger effect

size remain to be found

family-­‐based  linkage   GWAS  Sequencing  

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SUMMARY 1.  Both forms of ID are typical complex diseases, with

polygenic inheritance and strong environmental effects 2.  Crohn’s may be more “genetic” than UC 3.  Genes/pathways are shared in IBD and with other

autoimmune diseases – frequently suggesting similar therapeutic approaches

4.  Differing CD and UC HLA associations support an inflammatory and autoimmune disease, respectively

5.  Some/many risk variants for IBD may be protective variants for historical infections of great consequence (e.g., mycobacteria/leprosy)

6.  Genetic findings have done little for diagnostics; but therapeutic potential seems vast, and little exploited so far