Scientific Abstract
Proposal No. IBD-0125P
Principal Investigator: Ben-Zion Levi, Ph.D.
Applicant Organization: Technion - Israel Institute of Technology (Haifa, Israel)
Project Title: Association between Nramp1 polymorphisms and Crohn’s disease in Israeli Jewish population
Period of Award: August 1, 2004 - July 31, 2005
A putative association between Natural Resistance-Associated Macrophage Protein 1 (Nramp1) promoter polymorphism and Crohn’s disease (CD) was recently reported. Nramp1 is a proton/ divalent cation antiporter exclusively expressed in monocyte/ macrophage cells with a unique role in innate resistance to intraphagosomal pathogens. In humans, CD is linked to specific Nramp1 alleles harboring polymorphism at the promoter region resulting in irregular DNA structure. This may affect the DNA binding capacity of transcription factors leading to the abnormal expression of Nramp1.
We have recently shown that the transcription factor Interferon Regulatory Factor 8 (IRF-8) is indispensable for the regulated expression of Nramp1. This factor is expressed solely in macrophage and dendritic cells and plays a key role in their maturation. Taken together, it is extremely important and interesting to explore IRF-8’s contribution to inflammatory bowel disease (IBD) in general and CD in particular through the regulated expression Nramp1 as an additional genetic factor that affects the etiology of CD in patients with a specific genetic background.
The hypothesis of the proposed research is based on accumulating evidence that points to a pivotal regulatory role for IRFs in general, and IRF-8 in particular, in the etiology of CD. In this brief proposal, we would like to search for association between Nramp1 promoter polymorphism and CD in the Israeli Jewish population. We propose to expand the survey for genetic factors in the etiology of CD to include a wide scale genetic search for an association between Nramp1 promoter polymorphism and CD. A large DNA collection of ethnic Israeli population samples obtained from both CD and UC patients as well as from healthy donors will be employed. These DNA samples (200 each) have already been screened for NOD2/CARD15 mutations and will be subject to Nramp1 promoter polymorphism analysis. This analysis will allow us not only to draw an association between Nramp1 polymorphism and CD, but also to determine Nramp1 allele frequency in the Israeli Jewish population and to see if there is any correlation to ethnic background. Further, since the entire DNA samples were already analyzed for NOD2/CARD15 haplotype/mutations, this analysis will enable us to draw any correlation between these two genetic traits.
This brief research grant will explore the distribution of Nramp1 promoter alleles among a population of Israeli Jewish patients that have Crohn's disease or ulcerative colitis in comparison to healthy donors. We expect to identify an association between a specific allele of Nramp1 and Crohn's disease. This study will help individuals with Crohn's disease by improving diagnostics through the identification of new genetic defects associated with the disorder.