Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.815750
Title: HLA-B27 and related genes in the aetiopathogenesis of ankylosing spondylitis
Author: Higgins, Colleen Michele
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 1990
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Abstract:
It is well established that there is a very strong association between the MHC class I transplantation antigen HLA-B27 and the inflammatory disease ankylosing spondylitis (AS). It is unclear if HLA-B27 is directly involved in the development of AS or if it is linkage disequilibrium with another gene and HLA-B27 is a marker for this true disease gene. Restriction fragment length polymorphism (RFLP) analysis was used to examine whether a particular variant of the HLA-B27 gene is associated with the disease in English and Polish populations. Using a probe from the 5' region of a HLA-B27 gene, a 14Kbp PvuII fragment was found that was more common in English HLA-B27+AS+ than HLA-B27+AS-subjects (p<0.01) suggesting an involvement for this fragment in disease development. A PvuII fragment of 8.9Kbp was identified in more English HLA-B27+AS- than HLA- B27+AS+ subjects (p<0.01). While a trend could be seen for the Polish group, the number of HLA- B27 positive healthy individuals was too small for statistical analysis. This fragment is thought to be the same as the 9.2Kbp PvuII RFLP reported by McDaniel et al (1987) to be more frequent in HLA- B27 positive patients than in HLA-B27 positive healthy controls. Differences in hybridization patterns were observed in this study compared with those observed by McDaniel et al (1987) with supposedly similar probes. For example, in this study the 8.9Kbp PvuII fragment was not detected with probes derived from the 3' region of the HLA-B27 gene. While the different hybridization patterns may explain the conflicting results, it is also possible that population differences exist Analysis of the available tissue types showed an association between the 8.9KbpPvuII RFLPwith HLA-A3/A9, confirming the finding of Ahearn et al (1989). In addition, no disease associated RFLP was identified using probes derived from the 3' region of the HLA-B27 locus as well as the restriction enzymes EcoR1 and HindIII. The possibility that another gene is involved in the development of AS was also considered. Due to its proximity to the HLA-B locus, the tumour necrosis factor-α (TNF-α) gene was thought to be a possible candidate for such a gene. In order to determine the level of polymorphism of the human TNF-α gene, genomic DNA from healthy individuals were digested with 26 different restriction enzymes and hybridized with a probe for the TNF-α gene. No RFLP was detected with any of the enzymes used. In addition, a small study of English and Polish patients and controls also showed that no disease associated PvuII, EcoR1 of HindIII RFLP with the TNF-α gene. This suggests that no gross structural changes have occurred within the TNF-a locus that gives rise to AS. To examine differences in the HLA-B27 nucleotide sequence that are not revealed as RFLPs, the HLA-B27 gene of the HLA-B*2705 subtype was cloned from an AS patient heterozygous for this allele. This ensured that a HLA-B27 gene of disease haplotype was isolated. Comparisons with published nucleotide sequences of other HLA-B27 genes isolated from healthy individuals and AS patients did not reveal any differences in the predicted amino acid sequence. This suggests that alterations in the HLA-B27 antigen do not play a role in the development of AS.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.815750  DOI: Not available
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