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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2012 by Medical College of Wisconsin
Sponsor:
Information provided by (Responsible Party):
Michael Stephens, Medical College of Wisconsin
ClinicalTrials.gov Identifier:
NCT00783575
First received: October 29, 2008
Last updated: June 22, 2012
Last verified: June 2012
  Purpose

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
Crohn's Disease
Ulcerative Colitis
Inflammatory Bowel Disease

Study Type: Observational
Study Design: Observational Model: Family-Based
Time Perspective: Prospective
Official Title: Genetic Markers as Predictors of Phenotypes in Pediatric Onset Crohn's Disease

Resource links provided by NLM:


Further study details as provided by Medical College of Wisconsin:

Primary Outcome Measures:
  • Genotype a cohort of IBD children for 4 NOD2/CARD15 mutations. [ Time Frame: Study completion ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]

Biospecimen Retention:   Samples With DNA

DNA extraction, serology


Estimated Enrollment: 1500
Study Start Date: October 2002
Estimated Study Completion Date: January 2015
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Groups/Cohorts
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.

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.

  Eligibility

Ages Eligible for Study:   up to 18 Years
Genders Eligible for Study:   Both
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.

Criteria

Inclusion Criteria:

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

Exclusion Criteria:

  • Diagnosis during non-pediatric age.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00783575

Contacts
Contact: Michael C Stephens, MD 414-266-3690 mstephen@mcw.edu

Locations
United States, Wisconsin
Children's Hospital of Wisconsin Recruiting
Milwaukee, Wisconsin, United States, 53226
Principal Investigator: Michael C Stephens, MD         
Sub-Investigator: Ellen Blank, MD         
Sub-Investigator: Subra Kugathasan, MD         
Sub-Investigator: Alfonso Martinez, MD         
Sub-Investigator: Joshua Noe, MD         
Sub-Investigator: Grzegorz Telega, MD         
Sub-Investigator: Steven Werlin, MD         
Sponsors and Collaborators
Medical College of Wisconsin
Investigators
Principal Investigator: Michael C Stephens, MD Medical College of Wisconsin
  More Information

Publications:
Podolsky, D.K., Inflammatory bowel disease (First of two parts). N Engl J Med, 1991. 325: p. 928-937.
Podolsky, D.K., Inflammatory bowel disease (Second of two parts). N Engl J Med, 1991. 325: p. 1008-1016.
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.
Cosgrove, M., R.F. al-atia, and H.R. Jenkins, The epidemiology of paediatric inflammatory bowel disease. Arch Dis Child, 1996. 74: p. 460-61.
Orholm, M., et al., Investigation of inheritance of chronic inflammatory bowel disease by complex segregation analysis. Br Med J, 1993. 306.
Rioux, J.D., M.J.Daly, and M.S.Silverberg, Genetic variation in the 5q31 cytokine cluster confers susceptibility to Crohn's disease. Nat Genet, 2001. 29: p. 223-228.

Responsible Party: Michael Stephens, Assistant Professor of Pediatrics, Medical College of Wisconsin
ClinicalTrials.gov Identifier: NCT00783575     History of Changes
Other Study ID Numbers: CHW 02/142, HRRC 446-02
Study First Received: October 29, 2008
Last Updated: June 22, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by Medical College of Wisconsin:
Crohn's disease
Ulcerative colitis
Inflammatory bowel disease
NOD2,CARD 15 mutations

Additional relevant MeSH terms:
Crohn Disease
Colitis
Ulcer
Colitis, Ulcerative
Intestinal Diseases
Inflammatory Bowel Diseases
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Colonic Diseases
Pathologic Processes

ClinicalTrials.gov processed this record on September 30, 2014