Twin studies and familial clustering of inflammatory bowel disease (IBD) provide strong evidence that IBD is a heritable trait with complex genetics. Preliminary studies show that the investigators have found and replicated a novel IBD linkage on chromosome 3p, and linkage disequilibrium between IBD and two adjacent microsatellites within the chromosome 3p region of interest. Transmission (to affected individuals) of an allele at each of the two adjacent chromosome 3p microsatellites partitions the linkage evidence at the chromosome 3p IBD microsatellite that show linkage and linkage disequilibrium with IBD should make possible identification of the IBD gene on chromosome 3p microsatellites that show linkage and linkage disequilibrium with IBD should make possible identification of the IBD gene on chromosome 3p, and in so ding, also simply the search for the IBD2 gene. The investigators will carry out a fine mapping exercise over a 3 megabase region centered on the two adjacent chromosome 3p microsatellites that are in linkage disequilibrium with IBD. They will develop a 20 kilobase grid of single nucleotide polymorphism and microsatellite markers across the 3 megabase region, genotype 1, 151 members of 297 independent IBD nuclear families at these loci, and use a variety of methods to analyze the patterns of linkage disequilibrium. Since the investigators have at their disposal whole families, rather than examining single markers one at a time they will use more powerful haplotype- based approaches to identify the interval that is most likely to contain the IBD-predisposing genetic variant through the comparison of haplotypes that are transmitted and not transmitted to affected individuals. Gene(s) that are physically mapped to the interval defined by fine mapping and other candidate gene(s) will be resequenced in twenty-four unrelated, IBD-affected individuals. Polymorphisms that are identified within the gene(s) will be genotyped in the whole sample of IBD nuclear families. These data will then be analyzed with an extension of the transmission/disequilibrium test that calculates the significance of linkage disequilibrium independent of linkage. IBD-associated genetic variants that are identified in this project will be targeted for study in future genetic epidemiological and functional studies.
| Barmada, M Michael; Brant, Steven R; Nicolae, Dan L et al. (2004) A genome scan in 260 inflammatory bowel disease-affected relative pairs. Inflamm Bowel Dis 10:15-22 |
| Barmada, M Michael; Brant, Steven R; Nicolae, Dan L et al. (2004) A genome scan in 260 inflammatory bowel disease-affected relative pairs. Inflamm Bowel Dis 10:513-20 |
| Brant, Steven R; Panhuysen, Carolien I M; Nicolae, Dan et al. (2003) MDR1 Ala893 polymorphism is associated with inflammatory bowel disease. Am J Hum Genet 73:1282-92 |
