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

Ulcerative Colitis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT00783575
• Other study ID #: CHW 02/142
• Status: Withdrawn
• Phase: N/A
• First received: October 29, 2008
• Last updated: August 21, 2015
• Start date: October 2002
• Est. completion date: January 2015

Study information

• Verified date: August 2015
• Source: Medical College of Wisconsin
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: January 2015
• Est. primary completion date: January 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 18 Years

Eligibility

Inclusion Criteria:

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

Exclusion Criteria:

• Diagnosis during non-pediatric age.

Study Design

Observational Model: Family-Based, Time Perspective: Prospective

Related Conditions & MeSH terms

• Colitis, Ulcerative
• Crohn Disease
• Crohn's Disease
• Inflammatory Bowel Disease
• Inflammatory Bowel Diseases
• Intestinal Diseases
• Ulcerative Colitis

Locations

Country	Name	City	State
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin

Sponsors (1)

Lead Sponsor	Collaborator
Medical College of Wisconsin

Country where clinical trial is conducted

United States, 

References & Publications (25)

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* Note: There are 25 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Genotype a cohort of IBD children for 4 NOD2/CARD15 mutations.		Study completion	No
Secondary	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		Study completion	No