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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00783575
Recruitment Status : Withdrawn (PI has left institution)
First Posted : October 31, 2008
Last Update Posted : August 24, 2015
Information provided by (Responsible Party):
Medical College of Wisconsin

Brief Summary:

The purpose of this study is to look for the NOD2 gene in children with Inflammatory Bowel Disease (IBD) and their parents. We hope to understand this NOD2 gene better by determining whether children that have IBD have the NOD2 gene. In those with the NOD2 gene, we want to see if the type of gene abnormality predicts the nature of their disease and if the genetic information helps doctors decide what therapies and/or treatments to use for their patients. We also hope to explore the relationships between known serologic markers of IBD (ASCA, pANCA, ompC) and the clinical characteristics and course of children with IBD.

About 1500 children and as many of their parents as possible will take part in this study. Children who are newly diagnosed with IBD as well as children that are being seen in the Children's Health System are eligible to participate in this study. We are looking for children 18 years old or younger to participate. If possible, we would also like both parents of the child to participate.

Condition or disease
Crohn's Disease Ulcerative Colitis Inflammatory Bowel Disease

Detailed Description:

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.

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Study Type : Observational
Actual Enrollment : 0 participants
Observational Model: Family-Based
Time Perspective: Prospective
Official Title: Genetic Markers as Predictors of Phenotypes in Pediatric Onset Crohn's Disease
Study Start Date : October 2002
Estimated Primary Completion Date : January 2015
Estimated Study Completion Date : January 2015

Inflammatory Bowel 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.

Primary Outcome Measures :
  1. Genotype a cohort of IBD children for 4 NOD2/CARD15 mutations. [ Time Frame: Study completion ]

Secondary Outcome Measures :
  1. Statistical analysis of phenotype and genotype correlation in a cohort of pediatric Inflammatory Bowel Disease children with or without a family history of Inflammatory Bowel Disease [ Time Frame: Study completion ]

Biospecimen Retention:   Samples With DNA
DNA extraction, serology

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Children from Southeast Wisconsin diagnosed with Inflammatory Bowel Disease at Children's Hospital of Wisconsin and their biological parents.

Inclusion Criteria:

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

Exclusion Criteria:

  • Diagnosis during non-pediatric age.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00783575

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United States, Wisconsin
Children's Hospital of Wisconsin
Milwaukee, Wisconsin, United States, 53226
Sponsors and Collaborators
Medical College of Wisconsin
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Principal Investigator: Michael C Stephens, MD Medical College of Wisconsin

Hampe, J. and S. Schrieber, A genome-wide search identies potential susceptibility loci for Crohn's disease. Am J Hum Genet, 1999. 64: p. 808-16.
Calkins, B.M., Inflammatory Bowel Diseases, in Digestive Diseases in the United States: Epidemiology and Impact, J.E. Everhart, Editor. 1994, U.S. Government Printing Office: Washington D.C. p. 509-550.

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Responsible Party: Medical College of Wisconsin Identifier: NCT00783575     History of Changes
Other Study ID Numbers: CHW 02/142
First Posted: October 31, 2008    Key Record Dates
Last Update Posted: August 24, 2015
Last Verified: August 2015
Keywords provided by Medical College of Wisconsin:
Crohn's disease
Ulcerative colitis
Inflammatory bowel disease
NOD2,CARD 15 mutations
Additional relevant MeSH terms:
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Crohn Disease
Colitis, Ulcerative
Intestinal Diseases
Inflammatory Bowel Diseases
Gastrointestinal Diseases
Digestive System Diseases
Colonic Diseases
Pathologic Processes