| Summary: | Firstly, the importance of corticosteroid resistance/dependence as a co-factor in disease progression was studied in a detailed 5-year inception cohort (1998-2003). Secondly, a risk score to stratify the likelihood of response to standard medical therapy (high dose corticosteroids) identifying 3 distinct risk groups – low, intermediate and high risk; based on 167 consecutive patients (largest series studied) with acute severe UC was developed. A novel robust model was formulated with a sensitivity/specificity of 85% and 75% respectively to predict failure of medical therapy. These initial studies have provided the assimilation of highly accurate phenotypic and follow-up data, permitting very detailed statistical analyses to be performed in subsequent genetic studies. In this study, allelic variations of the MDR1 gene were found to be implicated in disease susceptibility in UC, in particular extensive and severe disease subphenotype (p=0.003, OR 2.64 and T-allele, p=0.009, OR 1.70). Bi-directional haplotypic contribution to susceptibility in UC (with protective and susceptible haplotypes) was observed. The novel ‘gene-wide’ haplotype tagging approach confirmed a more significant association with UC (p=4.22x10-7) but not CD (p=0.22). The strongest association was with the sub-phenotype extensive UC (p=1.7 X 10-7), and critically dependent on one tSNP rs3789243 (p= 3.2 x 10-7 – 3.6 x 10-12). Significant and replicable association of haplotypic variations of the ABCC3/MRP3 gene (also involved in epithelial barrier defence) with IBD (p=0.00004, 1200 IBD and 700 controls) have now been demonstrated. The characterisation of these genes has implicated this novel class of transport proteins as important regulators of mucosal defence and is critical in determining susceptibility to inflammatory bowel disease.
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