1. Dr Miles Parkes, Cambridge Dr Hannah Gordon, London RSM and CCUK® 2015
Who gets IBD and Why?
Dr Miles Parkes, Cambridge
Dr Hannah Gordon, London
RSM and CCUK® 2015

2. Introduction Who? Why? Epidemiology
Heritability – twin and family studies
Genetics
Environment
Interface between Genes and Environment
Microbiota
Epigenetics

3. Prevalence UK prevalence 4/1000
620,000 affected within the UK (IBD Standards, CCUK® 2015)

4. Age All ages affected Peak incidence 15-30 years 2nd peak 50-80 years
Incidence rising in children
(Henderson 2012)

5. Sex
Men and women are affected almost equally

6. Race
Traditionally a disease of the West, rates of IBD remain high in Western Europe and North America (Cosnes 2011).
However all countries are affected with incidence rapidly rising in Asia.

7. Highest incidence of IBD in the World
Faroe Islands – 80 per 100,000 new cases diagnosed per year

8. Ethnicity and affluence
Ashkenazi Jews
Caucasians
Socio-economic status
Previously thought to be associated with affluence
Not replicated in all studies

9. Is Inflammatory Bowel Disease Heritable?
Heritability is the extent to which a trait is caused by our genes
How can we estimate heritability of IBD?
Family studies
Twin studies
Calculating extent identified genes explain IBD prevalence

10. Family studies
The greatest single risk factor for developing IBD is having one or more first degree family members diagnosed
Odds Ratio sibling risk vs population risk:
CD 25-42
UC 4-15
However, family history only reported in 5-16% IBD patients

11. Family studies
IBD in families shows concordance in
Behaviour
Location
Age of onset
IBD in families tends to present earlier and be more severe
BUT Families share similar environment as well as similar genes…..

12. Twin studies
Why?
Both identical and non-identical twins share similar environment
Identical share genetic code, twice as genetically similar
How?
Concordance of identical and non-identical twin pairs are compared
Difference between identical and non identical groups is crucial – ie almost all twin pairs share a history for chickenpox, but this is not inherited!

13. UK Twins with IBD: Pair concordance (UK IBD TAM 2014)
Previous twin cohorts (Tysk et al 1988, Halfvarson 2007, Brant 2011)
The second table shows the range of concordance rates from previous twin studies. European cohorts similar sample sizes. Dizygotic concordance rates are higher than previous cohorts and indeed outweighing that expected by non twin siblings by over 4 fold.
Crohn’s Disease
Ulcerative Colitis
Monozygotic
20-55%
3.6-17%
Dizygotic
0-3.6%
0-6.3%

14. Compare the genomes of people with IBD vs people without IBD
Genetic Studies
Compare the genomes of people with IBD vs people without IBD
=> identify gene variants associated with IBD
=> work out functional impact + how they predispose to IBD
(role for IBD Bioresource)
=> 1. clues re environmental triggers
2. ? ‘druggable’ targets

15. Genome Wide Association Scanning => Unbiased survey of whole genome
Genotype >0.5 million markers in thousands of cases + controls
Use stringent statistics to identify ‘associated’ SNPs i.e. with significantly different allele frequencies in cases vs controls
Identify genes mapping to same region
Study impact of associated gene variant on protein function in relevant
cell type

16. UKIBDGC and IIBDGC GWAS Studies
GWAS studies in IBD

17. GWAS meta-analysis + Immunochip deep replication
Jostins et al Nature 2012: International IBD Genetics Consortium
GWAS meta-analysis + Immunochip deep replication
163 discrete
risk loci
identified
Immunchip - 14,763 CD / 10,920 UC / 15,977 control subjects
GWAS - 6,333 CD / 6,687 UC / 15,056 control subjects

18. 163 genes and loci: What have we learned?
Large overlap between UC and CD
Jostins et al. Nature 2012

19. Franke et al Nature Genet 2010.
IL23R pathway Duerr et al Science 2006; Parkes et al Nature Genet 2007; Barrett et al Nature Genet 2008;
Franke et al Nature Genet 2010.
IFNgamma
IL-17
IL-6
TNF alpha
IL-12
p40
p35
IL-23
CCR6
p19
p40
Th 17
Th 1
STAT4
STAT3
Naive CD4+ve T Cell
ICOSL
JAK2
McKenzie et al.
TRENDS in Immunology 2006:27(1), 17-23
ICOS

20. Clinical impact…
A pipeline for drug discovery

21. Genes discovered ‘early’ have biggest effect: Odds ratio for CD according to NOD2 genotype
NOD2 not assoc with UC

22. 3 main mutations – all in LRR domain
NOD2 domains & mutations
CARD
NBD
LRR * *
* non-synonymous
§ frameshift - premature stop
3 main mutations – all in LRR domain

23. Autophagy

24. ATG16L1 ATG16L1 – a key component of autophagy
independent discovery in German, N American (NIDDK) and UK (WTCCC) CD GWA panels
Hampe et al Nature Genetics 2007
Rioux et al Nature Genetics 2007
WTCCC Nature 2007

25. Association at IRGM – another autophagy gene
Parkes et al. Nature Genetics 2007

26. The power of hypothesis-free GWAS
2 genes in same (previously unsuspected) pathway associated with CD susceptibility
= ATG16L1 and IRGM

27. Autophagy lysosome AH AH Phagophore cytoplasm Autophagolysosome
Autophagosome
Autophagolysosome

28. T300A
↑↑ cleavage of ATG16L1 by caspase 3 when latter is activated through TNF / metabolic / infection stress
↓↓ xenophagy
disrupted pathogen elimination
Murthy et al Nature 2014

29. Epithelial barrier loci - HNF4a E-cadherin...etc
GWAS studies in UC
UC-specific
Epithelial barrier loci -
HNF4a
E-cadherin...etc
Franke et al Nat Genet 2009
Fisher et al Nat Genet 2008
Silverberg et al 2009
UKIBDGC / WTCCC Nat Genet 2009

30. Epithelial barrier Increased permeability as risk for IBD
Allows commensals to breach epithelial barrier and activate mucosal immune system
Questions:
Why UC-specific?
What leaks through?

31. Overlap with other diseases
Fold enrichment
Ankylosing spondylitis
13.7
Psoriasis
13.4
Atopic dermatitis
12.2
Primary sclerosing cholangitis
11.6
Primary biliary cirrhosis
10.8
Rheumatoid arthritis
10.1
Celiac disease
Type 1 diabetes
9.9
Systemic lupus erythematosus
Multiple sclerosis
8.1
Asthma
7.6
Jostins et al. Nature 2012
... implicates Mycobacterial infection as a evolutionary selection pressure for IBD?

32. Rapid rise in IBD suggests environment is critical
Genes
Environment

33. Rise of IBD in the East
2-3 fold increase in IBD incidence in past years in several Asian countries
Mirrors increase seen in Western countries 50 years ago
More UC, although CD rapidly increasing
Only 3-10% report family history of IBD
Far outweighs what can be explained by new genetic mutations

34. Migration studies
Higher rates of IBD in Asians in Western Europe, Australia, Northern America
Second generation Asian migrants in Leicestershire had UC rates comparable to Caucasian British
Disease is as if not more severe, more likely to affect men, and less likely to affect outside the gut

35. Why the increase in Asia
Diet
Hygiene
Infection
Westernisation of lifestyle

36. Environmental factors
Lifestyle
Smoking
Diet
Low Exercise
Stress
Health
Childhood illness
Gastrointestinal infection
Atypical Mycobacterium
Appendicectomy
Early Environment
Emergency Caesarian
Breastfeeding
Medication
Aspirin
NSAIDS
Oral Contraception
Antibiotics

37. Diet Read made meals Polyunsaturated fats High sugar Low vegetable
Low fruit
Low fibre

38. Problems interpreting data on environmental factors
Correlation not cause and effect
Results vary between studies
Each factor conveys a relatively modest risk
Risk factors often not avoidable
Important to avoid guilt or blame

39. The Microbiome 100 trillion bacteria within gut
10x more cells than human body
Complex ecosystem
Implicated in health of all other organs
Cardiovascular disease
Depression
Obesity
Inflammatory Bowel Disease

40. HMP Nature 2013
Significant variation between individuals re taxa / species
BUT – key metabolic pathways are VERY stable in health

41. What influences composition of microbiota?
Genetics
Race
Early environment
Smoking
Diet
Antibiotics
Infection
Method of delivery
The microbiota influence mucosal immune development and homeostasis – disturbance may contribute to development of IBD.

42. Dysbiosis in Crohn’s Disease – incl ↓ diversity
Increased in CD
Sokol et al PNAS 2009
Decreased in CD
Gevers et al Cell Host and Microbe 2014

43. Is the bacterial dysbiosis secondary to bacteriophage ‘bloom’
Is the bacterial dysbiosis secondary to bacteriophage ‘bloom’? What functional elements are being transferred? What impact on host immunity?
Norman et al. Cell 2015

44. The Microbiota and IBD
Unclear whether changes happen before or after disease develops
Cause or correlation?

45. Can we change the microbiota?
Yes!
Dietary change from vegan to exclusively meat and dairy changes microbiota substantially in days
Some changes associated with meat diet were same as those associated with IBD
Smoking cessation changes microbiota
However
Once IBD has developed, prebiotics, probiotics and faecal transplant not yet shown to be a cure

46. Epigenetics
Epigenetics: programmed regulation of gene expression in response to environmental factors Epigenetic changes associated with CD and UC have been found in gut biopsies and blood Twin studies underway to further investigate

47. Conclusion: Anyone can get IBD Increased risks
Genetic susceptibility
Environmental triggers
Dysbiosis of microbiota
Epigenetic change
Why important to understand?
Prevention
Prediction and early diagnosis
Novel targets for treatment

48. The Jesse and Thomas TAM Family Foundation
UK IBD Genetics
Consortium