Date on Master's Thesis/Doctoral Dissertation

5-2004

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Physiology and Biophysics

Committee Chair

Galandiuk, Susan, 1957-

Committee Co-Chair (if applicable)

Joshua, Irving Gilbert

Author's Keywords

Health and environmental sciences; Biological sciences; Toll-like receptor; Inflammatory bowel disease; Crohn's disease; Myeloid differentiation factor; Ulcerative colitis

Subject

Inflammatory bowel diseases--Genetic aspects

Abstract

Inflammatory bowel disease (IBD) is a chronic autoimmune disorder that is subdivided into Crohn's disease (CD), ulcerative colitis (UC), and indeterminate colitis (IC). Epidemiological studies have proven that genetic variation increases susceptibility to IBD, with multiple abnormal genes combined with environmental factors being responsible for disease development. Characterization of these susceptibility genes remains of critical importance to improving understanding of IBD pathogenesis. The overall aim of this study is to discover new IBD susceptibility genes. The initial approach was to study a number of previously described IBD susceptibility loci through characterization of peak LOD score short tandem repeat markers using population- and family-based methods. The IBD1, IBD2, and IBD5 loci were shown to be associated with different forms of IBD in the study cohort. This work formed the basis of the next series of experiments, where the IBD2 locus was mapped in detailed. IBD2 was shown to be associated with IC, colonic CD and to some extent UC. Focus of this study then turned to two candidate genes: interleukin-1 receptor-associated kinase-M (IRAK-M), an inhibitor of the strongly proinflammatory Toll-like receptor pathway, and myeloid differentiation factor 88 (MyD88), an adaptor protein involved in macrophage apoptosis. These genes were selected on the basis of their biological plausibility and genomic location (within IBD2 and IBD9 respectively). The first phase of this study was to define candidate gene colonic mucosal expression levels in IBD, and to screen coding and regulatory regions for polymorphisms. Both genes were significantly over-expressed in IBD-affected mucosa, and contained a total of seven commonly occurring single nucleotide polymorphisms (SNPs). These polymorphisms were then characterized in the entire population to define disease-associations. SNPs within the 3'-untranslated region of "MyD88" were associated with late onset CD in patients with a family history of IBD. However, a number of concerns do exist regarding the low statistical power of these analyses. In contrast, "IRAK-M" is unlikely to play a role in IBD susceptibility in this population. In conclusion, preliminary evidence is presented to show that "MyD88" may be an IBD susceptibility gene. Its precise role in CD development will be clarified in further studies.

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