Crohns Disease

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Crohns Disease

• Public Health 256
• Molecular and Genetic Epidemiology
• Fall 2000

2
Natural History

• Inflammatory Bowel Disease (IBD)
• Crohns Disease (CD)
• Ulcerative Colitis (UC)
• Prevalence
• Occurrence
• Symptoms

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Inflammatory Bowel Disease

• Ulcerative Colitis
• Inflammation of the lining of the large intestine
  or colon
• Crohns Disease
• Inflammation extends deeper into the lining of
  the intestine and usually occurs in the first
  part of the large intestine (cecum) and the ileum

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Anatomy of IBD
Location of the ileocecal region cecum, ileum
and ileocecal valve
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Symptoms of IBD

• Loss of appetite
• Bloody diarrhea
• Abdominal pain
• Fever
• Growth failure
• Anemia

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IBD Occurrence

• Most often diagnosed between the ages of 15 and
  40 (30 between the ages of 10-19)
• About 2 in children under the age of 10
• A lesser peak between the ages of 50 and 80

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CD Incidence Rates

• CD 1-10 per 100,000/yr in the U.S.
• Incidence has been increasing slowly world-wide
• Highest rates in Scandinavian Countries and
  Scotland followed by England and North America
• Uncommon in developing countries

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Crohns Disease Hypothesis
Targan and Murphy, 1995

• LUMEN

Lumenal bacterial antigens/products
1
Mucosal immune system
Th1 v. Th2 response
Level/duration of cytokine response
Resistance to Normal downregulators
Tissue Injury/ineffective repair
2
4
5
3
Th2
Severity of disease
T
Th1
GENETIC SUSCEPTIBILITY

• 2 3 4
• Number of genes

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Heritability of CD

• Heritability is greater for CD than UC
• Strong evidence from twin studies, familial risk
  data, and segregation analysis
• Complex genetic trait as inheritance does not
  follow any simple Mendelian models.
• Recessive Model with reduced penetrance and
  polygenic multifactorial inheritance

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Genetics of CDFrom the OMIM http//www.ncbi.nlm
.nih.gov/entrez/query.fcgi?dbOMIM

• IBD has been linked to 16p12-q13 (IBD1), 12p13
  (IBD2) and 6p (IBD3).
• Hugot et al, 1996 identified the susceptibility
  locus to be centered around D16S409 and D16S419
• Cavanaugh, et al 1998 Australian families 1.7cM
  region between D16S409 and D16S753

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HLA and CD

• HLA class II DR or DQ alleles are associated with
  CD, and the DPB10401 allele was shown to be
  associated with CD as compared to UC. This
  association is not due to linkage disequilibrium
  with the previously defined DR/DQ regions, but
  represents an independent risk factor.

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Unknown Etiology of CD

• Infectious agent(s)?
• Vaccines?
• Diet (refined sugar and starch consumption)?
• Fast food?
• Perinatal infections?

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Molecular Genetics Leads to Cure

• Knowing the genes and related immunologic
  markers of a given patient would define subgroups
  and direct therapy to most effectively combat the
  array of abnormalities by separate, or sequential
  therapies. A goal for the future is to define
  the most central abnormalities, for example, Th1
  imbalance, and direct therapy to this point,
  bringing the inflammation into remission, and to
  follow with antigen(s)-specific therapy. (Targan
  and Murphy, 1995)

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Framework for looking at Crohns disease etiology
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Evaluating whether Crohns Disease might have a
genetic component . . . A) geographical variation
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Crohns disease on the rise - link to
industrialization??
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Evaluating whether Crohns Disease might have a
genetic component . . .
B) descriptive epidemiology ethnic
variations Ashkenazi Jews outside Israel gt
inside Israel Northern EuropegtNorth American
gtJapangtdeveloping countries
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Evaluating whether Crohns Disease might have a
genetic component . . .
C) family history 10 to 25 of probands have
positive family history D) familial
aggregation relative risk for CD in siblings
36.5 highest risk among first-degree
relatives Age adjusted risk estimate for
CD 3.9 of first degree relatives E) family
clustering risk of CD in sibs / risk of CD in
general population 15 35
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How familial studies have elucidated information
on Crohns
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How twin studies have elucidated information on
Crohns
Twin studies Sweden - twin registry - 44
pairs with IBD heritability of liability ( r
) proportion of variance of normally
distributed liability which is genetic range
0-1 r ? reflects the genetic contribution to
the disease manifestation monozygotic
twins r 1.0 (0.8 - 1.0) dizygotic twins
r0.47 (0.20-0.73)
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How twin studies have elucidated information on
Crohns
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How familial studies have elucidated information
on Crohns
Concordance between family members gt random
assortment age of onset within 10 years
(68) type of disease (88) Differentiating
aspects to familial disease as compared to
sporadic disease
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How epidemiology and its study designs have
elucidated some of the genetic aspects to Crohns
disease ...
A genetic heterogeneity model would hold that
Crohns disease is not a single disease but is
rather several, perhaps etiologically and
phenotypically distinct, diseases presenting a
similar clinical picture. Each of the individual
component disorders conceivably could be
inherited in a Mendelian, multigenic mode,
perhaps with environmental influences affecting
the expression of disease (Bayless, 1996)
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Complex Segregation Analyses of a Family Study
with 265 Patients With Crohn Disease and 5,387
Relatives Kuster, W., et al. Am J. Medical
Genetics (32)105-8, 1989
Suggests that a recessive gene with low
penetrance affects susceptibility to Crohn
disease.
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Segregation Analysis

• Issues
• mode of inheritance
• penetrance
• genetic heterogeneity

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• Public health implications and applications of
  understanding the genetics behind Crohns
  disease
• risk -- genetic anticipation
• treatment
• etiology - genetics vs. environment
• research studies