Final Progress Report

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.  Lay Summary

Inflammatory bowel diseases (IBDs) such as Crohn's disease or ulcerative colitis are chronic inflammatory disorders of the gastrointestinal tract. Multiple factors affect the onset of these diseases such as genetic mutations, gut flora, and the immune system. Numerous genetic studies and detailed screening of Crohn's disease and ulcerative colitis patients have revealed several susceptibility regions in the human genome. The role of genetic factors in the etiology of Crohn's disease has been supported by the studies of ethnic differences, familial aggregation, and twin and spouse data. With regard to ethnic variation, a consistently increased incidence and prevalence rate of Crohn's disease in the Jewish population has been documented. A recent advance is the identification of defective variants of a gene, termed NOD2/CARD15, which predisposes people to this disease. This gene is defective in 30%-50% of the patients suffering from Crohn's disease. This association of the NOD2/CARD15 gene and Crohn's disease has also been reported in Israeli Jewish patients. The Jewish population in Israel is composed of Ashkenazi and Sephardic Jews, groups that differ in their genetic background. The occurrence of Crohn's disease in Ashkenazi Jews is higher than in Sephardic Jews. Recent studies have identified an association between Crohn's disease and mutations in yet another gene termed Nramp1 (also known as SLC11A1). In humans, the aberrant expression of the Nramp1 gene is linked to a variety of infectious diseases including leprosy, pulmonary tuberculosis, visceral leishmaniasis, meningococcal meningitis, and HIV. It is also linked to autoimmune diseases such as rheumatoid arthritis and Crohn's disease. Interestingly, the genetic variations (termed alleles) are not in the gene but in a functional region adjacent to the gene that is essential for regulating its expression. This region is termed promoter region. The promoter acts like a light dimmer. Its DNA sequence dictates the ability of regulatory proteins that bind to it to initiate the expression of the gene.

We study the regulatory protein IRF-8, which binds to the promoter of Nramp1 and regulates its expression. Genetically inherited variations (polymorphism) in the DNA sequence of Nramp1 promoter can affect the binding of IRF-8 and subsequently lead to aberrant expression of Nramp1 resulting in the development of Crohn's disease in these individuals.

This proposed brief research was aimed to 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 expected to identify an association between a specific allele of Nramp1 and Crohn's disease. 131 samples of healthy donors and 131 samples of Crohn’s patients were analyzed. Four alleles were identified. ~70% carried allele 3, ~30% allele 2, ~1% allele 1 and less than 1% allele 5.There were no difference in allele frequencies between healthy donors and Crohn's disease patients. In addition, no correlation was found with mutations in NOD2/CARD15 and the phenotype of Crohn's disease. This led us to conclude that difference in Nramp1 promoter polymorphism plays no role in Crohn's disease in Ashkenazi Jews.