Genetic determinants of susceptibility to inflammatory bowel disease

The aim of this thesis was to advance the current knowledge of the genetic determinants ofsusceptibility to inflammatory bowel disease (IBD), and examine their effect on disease phenotype. A DNA source from 1071 well clinically characterized patients with IBD disease (644 Crohn's Disease (CD), 427 ulcerative colitis (UC» was established. This was used both alone and in combination with an existing IBD collection to investigate candidate susceptibility genes as well as the relationship between genotype and phenotype. . The previously reported association ofthe IBD5 locus with CD was investigated to try and identify the true disease susceptibility alleles. The coding regions of 10 genes in and around the IBD5 locus was resequenced in 24 CD cases and a linkage disequilibrium (LD) map was derived of the 27 single nucleotide polymorphisms (SNPs) detected. Ten SNPs representative oftheobserved LD groups, were tested. for CD association. L503F in SLC22A4 was the only nonsynonymous SNP significantly associated with CD (p=0.003J,· but was not associated with disease in the absence ofother markers ofthe 250 kb risk haplotype. Two other SNPs, rsl1242115 inIRFJ and rsl7166050 in RAD50, lying outside the 250kb risk haplotype, also showed CD association (p=O.O19 and p=0.0080, respectively). The contribution ofthe IBD5 locus as well as the 3 CARDJ5 variants that increase susceptibility to CD, on the clinical phenotype ofCD was investigated. A novel association of CARDJ5 variants was found with the presence of granulomas. The strong association of CARDJ5 variants with ileal disease was confirmed. Although CARDJ5 mutations were significantly associated with stenotic disease behaviour, this was not independent of an ileal disease location, and reflects the strong association between ileal location and stenotic behaviour. An association of the IBD5 locus with perianal disease location was observed. The association oftheABCBJ variants, C3435T and G2677T/A with IBD was examined in a large case-control cohort.The effect ofthese variants was further examined with respect to phenotypic and epidemiological characteristics. The 2677T allele was significantly increased in British UC cases compared with controls (45.2% vs. 39.6%; P = 0.034). In particular, the TT genotype was significantly associated with severe UC (odds ratio [OR] 1.90; 95% CI 1.01-3.55) and the use of steroids in UC (OR 1.77; 95% CI 1.08-2.88).EThOS - Electronic Theses Online ServiceGBUnited Kingdo