Genetic Markers as Predictors of Phenotypes in Pediatric Onset Crohn's Disease

Crohn's disease (CD) and ulcerative colitis (UC), collectively known as inflammatory bowel
disease (IBD) are chronic, life-long, destructive inflammatory conditions of the
gastrointestinal tract. IBD onset can occur at any age but the highest incidence occurs in
late childhood, adolescence and young adulthood. The incidence of IBD in children and
adolescents has significantly increased over the last 40 years. The precise factors
underlying IBD pathogenesis are not yet defined but may involve persistent bacterial
infection, a defective mucosal barrier, or an imbalance in the regulation of the immune
response. Epidemiologic studies from adult populations have identified a significant genetic
contribution to the etiology of CD, but simple Mendelian models of IBD inheritance are not
supported by segregation analysis. Taken together, these observations support a complex
immunogenetic model of IBD whereby genetically susceptible individuals harbor an aberrant
response to yet-unidentified environmental influences. Attempts to localize IBD
susceptibility genes through genome-wide linkage studies have identified putative loci on
chromosome 16. Recently 3 groups of investigators have shown that sequence variations within
the NOD2 gene (MIM 605956) on chromosome 16q12 were strongly associated with susceptibility
to CD. Attempts to link NOD2 mutations with disease phenotype have recently identified an
association between ileal specific-disease and patients with NOD2/ CARD 15 mutations. This
initial association between genotype and phenotype suggests that genetic factors influence
disease location. At this time the frequency of NOD2 gene mutations in a population based
sample, specifically in a cohort of newly diagnosed patients is not known. In addition, all
attempts to correlate genotype with CD phenotype have been performed in adults, and no data
has been generated in children. Identification of these mutations in children will be of
particular interest, as the presentation of initial disease will manifest disease in its
"purest" form, where the long duration of chronic inflammation typically seen in adult
patients will not have exerted influence on disease phenotype (i.e. stricture formation
secondary to longstanding, poorly controlled inflammation). Thus, genotype/phenotype
correlation in children in a prospective fashion will function to characterize NOD2/ CARD15
mutations in a general population, and will also begin the evaluation of disease progression
and prediction of disease severity and behaviour over time, with the starting point being
the time of diagnosis. This will have obvious clinical and therapeutic implications, and
will begin the process of linking disease genotype to optimal therapy. Therefore, our
central hypothesis: Identification of NOD2/ CARD 15 mutations in newly diagnosed CD children
will predict disease location, disease behaviour and will identify optimal approaches to
therapy. This will be tested by the following three Specific Aims.

1. Genotype a cohort of WI IBD children for 4 NOD2 / CARD 15 mutations.

2. Statistical analysis of phenotype and genotype correlation in a cohort of WI pediatric
IBD alliance children with or without a family history of IBD.

The Wisconsin pediatric IBD alliance was formed in January of 2000 to track all new
diagnoses of IBD occurring in children younger than age 18. This clinical consortium has
successfully recruited 100% of the pediatric GI specialists within Wisconsin to
prospectively record all new IBD diagnoses, in order to obtain a population based incidence
of CD and UC within the U.S. Between 1/1/00 and 12/31/01, we have identified 192 new cases
of IBD within the state. Sixty-five percent of these children were from Southeast Wisconsin,
and were diagnosed at Children's Hospital of Wisconsin. In addition to these newly diagnosed
children, a cohort of 294 additional pediatric IBD children followed at the Children's
Hospital of Wisconsin will serve as a reference population. The focus of this proposal will
be to correlate genetic influence on the clinical disease course and behavior using a
molecular classification of pediatric CD children in a population based pediatric cohort.
This DDC grant will allow the PI and the co-investigator to generate sufficient preliminary
data in the under-researched area of pediatric CD and to continue this investigation for
support from national foundations (CCFA) and /or the NIH.

Inclusion Criteria:

- Confirmed diagnosis of Inflammatory Bowel Disease (Crohn's Disease, ulcerative
colitis or indeterminate colitis).

Exclusion Criteria:

- Diagnosis during non-pediatric age.