In this thesis, an <i>in silico</i> investigation of available online microarray data found that normal colon, polyps and CRC have distinct gene expression patterns and that several key inflammation-related genes are up-regulated in polyps. This was also the findings of a pilot microarray study using Affymetrix human GeneChip<sup>®</sup> technology on normal colon and polyps biopsied from one individual. Validation of the microarray data for <i>IL-1B</i> and <i>il-8</i> was performed by RT-PCR and also revealed an overall up-regulation of these genes in polyp compared to normal colon. A CRC case-control study was then used to assess the role of pro-inflammatory single nucleotide polymorphisms (SNPs) in <i>IL-1B (-31 T/C), </i>TNF-A<i> (-308 G/A), TGF-B </i>(-509 C/T) and <i>IL-10</i> (-592 C/A, -1082 G/A) in sporadic CRC in the North East of Scotland. Their interaction with aspirin use was also investigated. Whilst statistically significant associations were not found between any of the SNPs and CRC alone, a statistically significant halving in risk of CRC (OR, 0.50; 95% CI, 0.27-.097) was found in carriers of the variant <i>IL-10-592</i> A allele who were regular aspirin users. Finally, the frequencies of 2 promoter, one exonic and one 3’-UTR <i>COX-2</i>SNPs were assessed in a Scottish population. The -899 and -197 <i>COX-2</i> promoter SNPs were not identified but the allele frequencies of the exon-3 and 3’UTR <i>COX-2</i> SNPs were similar to those reported in previous Caucasian studies. Further analysis including the <i>COX-2 </i>-765 G>SNP showed that -765 GG homozygotes infected with <i>H. pylori</i> had a significantly increased risk of developing pre-malignant changes of gastric cancer (OR 5.7, 95% CI, 2.3-14.1). This result is in keeping with previous studies which have suggested that the variant C allele is associated with reduced COX-2 suppression and inflammatory response.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:440593 |
| Date | January 2006 |
| Creators | Macarthur, Mairi |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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