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

August 21, 2015 updated by: Medical College of Wisconsin

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.

Study Overview

Status

Withdrawn

Conditions

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.

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

Study Type

Observational

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

United States
- Wisconsin
  - Milwaukee, Wisconsin, United States, 53226
    - Children's Hospital of Wisconsin

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 18 years (Child, Adult)

Accepts Healthy Volunteers

Genders Eligible for Study

All

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.

Description

Inclusion Criteria:

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

Exclusion Criteria:

Diagnosis during non-pediatric age.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Number of groups / cohorts

Cohorts and Interventions

Group / Cohort
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Genotype a cohort of IBD children for 4 NOD2/CARD15 mutations. Time Frame: Study completion	Study completion

Secondary Outcome Measures

Outcome Measure	Time Frame
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	Study completion

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Medical College of Wisconsin

Investigators

Principal Investigator: Michael C Stephens, MD, Medical College of Wisconsin

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2002

Primary Completion (Anticipated)

January 1, 2015

Study Completion (Anticipated)

January 1, 2015

Study Registration Dates

First Submitted

October 29, 2008

First Submitted That Met QC Criteria