Ulcerative colitis (UC) and Crohn's disease (CD), collectively known as inflammatory
bowel disease (IBD) are common, chronic inflammatory disorders of the intestines. The
pathogenesis and subsequent clinical course of IBD remain unclear; although, inter¬
relating factors such as environment triggers, dysregulated immune response, defective
gut barrier defence, variability of drug response and genetic susceptibility all contribute.
The current work described in this thesis involves a series of clinical and genetic studies
investigating their respective roles in determining susceptibility and course in UC.
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). This study
demonstrated remarkable concordance with older series and paediatric cohorts suggesting
a defined phenomenon within the innate response to corticosteroids. 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 critically
provided the assimilation of highly accurate phenotypic and follow-up data, permitting
very detailed statistical analyses to be performed in subsequent genetic studies. The
multidrug resistance gene (MDR1 gene-encoding P-glycoprotein 170, an epithelial efflux
transporter protein) was studied in detail due to its potential role in conferring
susceptibility (based on knock-out animal models and genomic position within IBD locus
of susceptibility) and its function in corticosteroid resistance. 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. In this study, bi-directional haplotypic contribution to susceptibility in
UC (with protective and susceptible haplotypes) was observed. This led to a more
rigorous analysis of this gene by the application of the novel 'gene-wide' haplotype
tagging approach, confirming a more significant association with UC (p=4.22xl0"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). This catalysed further rational approaches to study the genetic variations of the genes
involved in xenobiotic-metabolism and epithelial transport such as the ATP-binding
cassette (ABC) efflux transporters and respective transcriptional regulators in our cohort.
Further 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) was also shown. The characterisation of these genes in a
hitherto unknown pathway regulated by key transcriptional regulators such as PregnaneX receptor (PXR) has now implicated this novel class of transport proteins as important
regulators of mucosal defence and as critical in determining susceptibility to
inflammatory bowel disease
