Genetic Associations in Ankylosing Spondylitis

McGarry, Frances (2001) Genetic Associations in Ankylosing Spondylitis. MSc(R) thesis, University of Glasgow.

Full text available as:
[img]
Preview
PDF
Download (29MB) | Preview

Abstract

Ankylosing spondylitis is a common inflammatory arthritis that is characterised by inflammation of the spine and sacroiliac joints. The genetic association between AS and the MHC Class I gene B27 is one of the strongest disease associations known, however the evidence points to AS being an oligogenic disease. The aim of this study was to investigate several candidate genes that may contribute to the susceptibility to AS. The MHC Class II region is a highly polymorphic area where associations with particular alleles and other autoimmune diseases have been previously demonstrated. This study investigated the distribution of the MHC Class II DRbeta1 alleles and the DRbeta1*04 subtypes in a large well defined group of AS patients in comparison to both normal healthy controls and HLA B27 positive healthy controls all from the West of Scotland. A significant increase in the distribution of the DRbeta1*01 alleles was seen in the AS patients in comparison to both control populations. No significant differences were seen in the distribution of the DRbeta1*04 subtypes between the AS patients and the B27 positive controls. The TNF genes lie within the MHC Class III region on chromosome six in close proximity to the B27 gene. There are several polymorphic sites within the TNF genes, some of which have been linked to differences in production of the TNF proteins. TNF is an important pro-inflammatory cytokine and it has been suggested that increased levels of TNF could contribute to disease pathogenesis. Six different polymorphic sites were investigated in total. A significant increase in the 1* allele at the -308 site within the TNF promoter was seen in the AS patients compared to the B27 positive controls. Other associations were seen at other sites between the patients and the normal population but they would appear to be linked to the presence of B27 and not to the disease. None of the associations demonstrated would appear to be with any of the alleles linked to increased production of TNF. Recent whole genome screens have highlighted areas other than the MHC that may have a role to play in susceptibility to disease. One in particular is on chromosome two where the IL-1 genes lie. The IL-1 genes are also important pro-inflammatory cytokines where particular alleles have been associated with other autoimmune diseases. Three sites were investigated, one within the IL-1 alpha gene, one within the IL-1 beta gene and the third within the natural antagonist IL-1 receptor antagonist. No associations were seen in the IL-1 alpha or IL-1 beta, however a significant increase in the carriage of the 2* allele of the IL-1 receptor antagonist 86 base pair variable number tandem repeat was demonstrated in the AS patients compared to B27 positive controls. This allele has previously been shown to predispose to increased levels of the anti-inflammatory IL-I receptor antagonist. Overall this study has demonstrated three different associations at three different loci, one within the MHC class II region, one within the MHC class III and one within the IL-1 region. This study has also demonstrated the possible existence of extended haplotypes that could cross the TNF locus into the MHC Class II region that would incorporate the HLA B27 gene. Large family studies would be required to confirm this finding. In conclusion none of the associations demonstrated in this study are with any of the alleles that have previously been linked to increased pro-inflammatory cytokines. In fact it could be hypothesised that the associations demonstrated in this study could in theory lead to a reduced pro-inflammatory response.

Item Type: Thesis (MSc(R))
Qualification Level: Masters
Keywords: Genetics, Immunology
Date of Award: 2001
Depositing User: Enlighten Team
Unique ID: glathesis:2001-75744
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 19 Nov 2019 18:17
Last Modified: 19 Nov 2019 18:17
URI: http://theses.gla.ac.uk/id/eprint/75744

Actions (login required)

View Item View Item

Downloads

Downloads per month over past year