Who gets IBD and Why?

Dr Miles Parkes, CambridgeDr Hannah Gordon, London

RSM and CCUK® 2015

Introduction

• Who?• Epidemiology

• Why?• Heritability – twin and family studies• Genetics• Environment• Interface between Genes and Environment

• Microbiota• Epigenetics

Prevalence

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

Age

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

Sex

Men and women are affected almost equally

RaceTraditionally 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.

Highest incidence of IBD in the World

Faroe Islands – 80 per 100,000 new cases diagnosed per year

Ethnicity and affluence

• Ashkenazi Jews• Caucasians• Socio-economic status

• Previously thought to be associated with affluence• Not replicated in all studies

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

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 4-15However, family history only reported in 5-16% IBD patients

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…..

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!

Pair concordance (UK IBD TAM 2014)

Previous twin cohorts (Tysk et al 1988, Halfvarson 2007, Brant 2011)

Crohn’s Disease Ulcerative Colitis

Monozygotic 20-55% 3.6-17%

Dizygotic 0-3.6% 0-6.3%

UK Twins with 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

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

GWAS studies in IBD

UKIBDGC and IIBDGC GWAS Studies

Jostins et al Nature 2012: International IBD Genetics Consortium

GWAS meta-analysis + Immunochip deep replication

Immunchip - 14,763 CD / 10,920 UC / 15,977 control subjectsGWAS - 6,333 CD / 6,687 UC / 15,056 control subjects

163 discreterisk loci

identified

163 genes and loci: What have we learned?

Large overlap between UC and CD

Jostins et al. Nature 2012

IL23R pathwayDuerr et al Science 2006;

Parkes et al Nature Genet 2007;Barrett et al Nature Genet 2008;Franke et al Nature Genet 2010.

p40

p40

p35

p19

IL-12

IL-23

McKenzie et al.

TRENDS in Immunology 2006:27(1), 17-23

STAT4 STAT3

Th 1Th 17

IFNgamma

IL-17

IL-6

TNF alpha

Naive CD4+ve T Cell

JAK2

CCR6

ICOSICOSL

Clinical impact…

A pipeline for drug discovery

Genes discovered ‘early’ have biggest effect: Odds ratio for CD according to NOD2 genotype

Hetero-zygote

Homo-zygous

Compound Het

Hugot 3 38 44

Ogura 1.5 17 § only

Hampe 2.6 42 § only

Ahmad 2.4 9.8 29.3

NOD2 not assoc with UC

CARD 1 2 NBD LRR

* * §

NOD2 domains & mutations

* non-synonymous§ frameshift - premature stop

3 main mutations – all in LRR domain

Autophagy

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

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

The power of hypothesis-free GWAS

• 2 genes in same (previously unsuspected) pathway associated with CD susceptibility

= ATG16L1 and IRGM

Autophagy

Phagophore cytoplasmAutophagosome

lysosome

Autophagolysosome

AH

AH

Murthy et al Nature 2014

• T300AÞ ↑↑ cleavage of ATG16L1 by

caspase 3 when latter is activated through TNF / metabolic / infection stress

Þ ↓↓ xenophagy Þ disrupted pathogen elimination

GWAS studies in UC

UC-specific • Epithelial barrier loci -

– HNF4a– E-cadherin...etc

Franke et al Nat Genet 2009Fisher et al Nat Genet 2008

Silverberg et al 2009UKIBDGC / WTCCC Nat Genet 2009

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?

... implicates Mycobacterial infection as a evolutionary selection pressure for IBD?

Jostins et al. Nature 2012

Overlap with other diseases

Disease 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 10.1

Type 1 diabetes 9.9

Systemic lupus erythematosus 9.9

Multiple sclerosis 8.1

Asthma 7.6

Rapid rise in IBD suggests environment is critical

Genes

Environment

Rise of IBD in the East2-3 fold increase in IBD incidence in past 10-20 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

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

Why the increase in Asia

• Diet• Hygiene• Infection

Westernisation of lifestyle

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

Diet

Read made meals

Polyunsaturated fats

High sugar

Low vegetable

Low fruit

Low fibre

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

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

HMP Nature 2013

• Significant variation between individuals re taxa / species• BUT – key metabolic pathways are VERY stable in health

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.

Dysbiosis in Crohn’s Disease – incl ↓ diversity

Increased in CD

Decreased in CD

Gevers et al Cell Host and Microbe 2014

Sokol et al PNAS 2009

Is the bacterial dysbiosis secondary to bacteriophage ‘bloom’?

What functional elements are being transferred?

What impact on host immunity?

Norman et al. Cell 2015

The Microbiota and IBD

• Unclear whether changes happen before or after disease develops• Cause or correlation?

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

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 bloodTwin studies underway to further investigate

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

UK IBD Genetics Consortium

The Jesse and Thomas TAM Family Foundation