Genetic and Environmental Risks for IBD

Genetic and Environmental Risks for IBD CCFA April 26, 2014 Presented by: Name goes here April 30, 2014 TheoTheodore 1

Genetic and Environmental Risks for IBD Theodore M. Bayless, M.D. Director Emeritus Meyerhoff IBD Center.

Genetic and Environmental Risks for IBD

Estimated 1 Million Americans With IBD Ulcerative Colitis 50% Crohn s Disease 50% Approx 10% - 15% indeterminate colitis Cases per 100,000 persons Incidence (range) Prevalence (range) Ulcerative Colitis 2.2 15.6 38 246 Crohn s Disease 3.6 15.6 26 199

ULCERATIVE COLITIS AND CROHN S DISEASE

Inflammatory Bowel Disease IBD Ulcerative colitis Indeterminant Crohn s disease Distal Left-sided pancolitis Colitis Colitis Jejunoileitis Ileocolitis Ileitis Inflam Perf Stenotic

AGE AND SEX DISTRIBUTION OF IBD

IBD pathogenesis: 2014 Genetic Predisposition (innate immunity, barrier function, autoimmunity) IBD Mucosal Immune System (Immunoregulatory defect - disrupted homeostasis) Environmental Triggers (Lumenal bacteria, infection, barrier breakers)

Genes n DNA is composed of a sequence of four billion nucleotides. These sequences are found on 23 different chromosomes. Each person comes from 23 chromosomes from their mother (in the egg) and 23 chromosomes from their father (in the sperm). Males have an X and a Y chromosome Females have two X chromosomes

1985 1992: 554 Consecutive Crohn s Disease Patients at Johns Hopkins (TMB) 554 Crohn s Patients 120 (22%) IBD Family History (CD or UC) 96 (17%) CD Family History only 24 ( 4%) UC Family History only

IBD: Risk to Offspring n Lifetime Risk of IBD to a future child n One parent with IBD: 2 to 8% n One Jewish parent with IBD: ~ 10% n Multiple IBD relatives: > 10% n Both parents with IBD: 30-50% by age 21

Concordance of Phenotypes within CD Families Mother and Son, 13 Mother, ileitis Perforated at Age 28

Concordance of Phenotypes within CD Families Mother and Son, 26 Son, Perforated Ileum, 26

NOD2/CARD15: Mutations involved in 25% of Crohn s disease patients Younger age of onset 1,3 NOD2 Small bowel involvement 2-4 Fibrostenosing disease 1,5 20-40 fold increased risk for CD in NOD2 homozygotes Or compound heterozgotes

> 163 Gene Regions Identified for IBD Most risk for both Crohn and UC! 30% risk for other immune disease CD 30 IBD 110 UC 23 Immune Diseases 66 of 154 also IBD

IBD pathogenesis: 2013 Genetic Predisposition (innate immunity, barrier function, autoimmunity) IBD Mucosal Immune System (Immunoregulatory defect - disrupted homeostasis) Environmental Triggers (Lumenal bacteria, infection, barrier breakers)

Environmental Triggers of IBD Altered microflora Antibiotics Diet IBD Onset and Reactivation Altered mucosal barrier function and/or immunoregulatio Acute n infections NSAIDs Smoking Stress

Smoking: decreases risk for UC Increases risk for Crohn s disease Log of Relative Risk 0.4 0.3 0.2 0.1 0-0.1-0.2-0.3-0.4-0.5 ulcerative colitis Crohn's disease Risk of Disease in Smokers

Environmental Factors in Crohn s Disease Different in Ulcerative Colitis n Crohn s Disease n Ulcerative Colitis n Smoking Bowel Rest Antibiotics Appendectomy Acute Infection Chronic Infection Genes in CD: Innate Immunity/ Microbiome Interaction 0 0

ENVIRONMENTAL INFLUENCE: IBD PREVALENCE VARIES BY GEOGRAPHY: HIGH UC PREVALENCE IN SOUTH ASIANS MIGRATED TO UNITED KINGDOM UK prevalence 0.18% GEOGRAPHICAL PREVALENCE OF IBD N. India prevalence 0.04% Singapore Prevalence 0.02% Yang, Inflamm Bowel Dis, 2001 Lee, J Gastroenterol Hepatol, 2000

What about Westernization and higher latitudes that leads to greater IBD? n Western Diet? Higher intake of animal protein associated 3-fold risk 1 Milk derived fats associated with colitis in an animal model 2 n Modern bacterial selection? Antibiotic use associated with IBD? Cold Chain Hypothesis - (possible triggers like Listeria and Yersinia)? n Hygiene Effect? Crohn s protected by Vietnam service and POW status 3 Helminths can protect in animal models, can decrease TH1, TH2 and TH17 response and are being evaluated in clinical trials 4 n Low Vitamin D Lower UV radiation exposure in France and in US associated with Crohn s and with severity (Limketkai et al)

Messages n Individual with positive family history of Crohn s Disease or of Ulcerative Colitis is at increased risk for IBD n Risk to sibling is 5%; risk to offspring is 2-8% n Smoking increases the risk of developing Crohn s Disease ( Please, don t smoke )

Messages n Average age of diagnosis of IBD is 27. Onset in childhood or teenage in 20% n 90% of pre-pubscent CD patients have change in growth before dx made. n At least 10% of IBD have co-existent Irritable Bowel Syndrome (IBS) n A family history of Irritable Bowel Syndrome (IBS) is very common and is NOT a risk factor for IBD.

Genetic and Environmental Risks for IBD