Scientific Abstract

Proposal No. IBD-0267
Principal Investigator: Debby Laukens, Ph.D.
Applicant Organization:  Ghent University (Belgium)
Project Title:  Genetical genomics: A study of gene expression patterns in familial Crohn's disease
Period of Award:  March 15, 2009 – March 14, 2010

It is widely accepted that inflammatory bowel disease (IBD) emerges from the interaction of a number of genes inducing a state of intolerance towards luminal microflora. Well-known genetic susceptibility factors for Crohn’s disease (CD) are CARD15 and ATG16L1, and recently, single nucleotide polymorphisms (SNPs) at 19 new loci were identified in a large genome-wide association scan. How such SNPs determine susceptibility to IBD is not known, but one can speculate that some of them are likely to influence gene expression, either by interfering with binding of regulatory factors to DNA or by influencing transcript stability. The concept of heritable expression phenotypes has been established and could play a significant role during the onset of disease. Trying to uncover aberrant gene expression based on genetic markers could aid in the understanding of the disease and has potential to provide new therapeutic targets.

The term genetical genomics is used for the study of functional genetic variants and refers to genetic association of gene transcription, considering individual gene expression levels as quantitative traits. In the current project, we aim to identify genes that are differentially expressed in IBD most likely due to genetic variation rather than resulting from environmental influences or secondary disease-related phenomena. Full-transcriptome analysis using Agilent microarrays will be performed on RNA samples isolated from peripheral blood mononuclear cells of IBD patients with a family history of the disease as well as from their healthy relatives. Based on filtering procedures, ranking statistics and a heritability test, a set of candidate genes will be chosen and validated by quantitative PCR. After validation, the expression of the genes will be measured in mucosal IBD samples using an internal cDNA collection. The follow-up of this project involves the identification of genetic determinants regulating the expression of the selected candidate genes, using next generation sequencing. This approach will add to the understanding of how SNPs can functionally influence susceptibility to familial IBD.