Finding genes that lead to an increased susceptibility towards complex genetic disorders would be of enormous benefit to both individuals and society. These genes would give an insight into disease mechanism and could potentially lead to improvements in drug selection for patients, reveal novel biology pathways for drug targeting, allow clinical prediction of likely disease progression and reduce the inappropriate treatment of patients. Here I present four publications that document the progressive search for candidate susceptible disease genes for rheumatoid arthritis (RA). Starting with a whole genome screen (WGS), locating de novo regions of the genome likely to harbour casual genes, this is followed by a replication study, confirming the regions of interest. The discovery study confirmed the known association between RA and the HLA region, and generated 10 other putative candidate regions worthy of further investigation. Six of these regions overlapped with other published RA WGS (1q, 3p, 6q, 1Oq, 14q and 16p) and four were specific to my UK study (4p, 7p, 21p and Xq). Replication analysis in the 10 candidate regions, genotyped in an independent cohort, failed to validate any of the initial findings. This is probably due to type 1, false positive, errors in the discovery study 6 and a lack of power in the replication cohort. Stratification analysis did, however, reveal regions of the genome linked to a more severe, younger age of onset disease. Two of these regions, on 1q and 16p, contained strong candidate genes, FCRL3 and MHC2TA, with reported positive association to RA in Japanese and Swedish cohorts respectively. Two of my subsequent papers presented here investigate the associations between these 2 strong candidate genes and RA in our UK cohort. No association was found for any polymorphism tested, including the reported functional changes, for either FCRL3 or MHC2TA in our UK cohort. This may indicate population specificity for RA causal genes, or that the initial reported association was a false positive.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:557129 |
| Date | January 2007 |
| Creators | Eyre, Stephen |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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