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Title: Cytokine gene polymorphisms and their clinical relevance
Author: Reynard, Mark
ISNI:       0000 0001 3514 5267
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2002
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This thesis describes work investigating genetic polymorphism in human cytokine genes, many of which are located within regulatory areas. These polymorphisms may influence the production of cytokine and have effects on HSCT and infectious disease. The following cytokine gene polymorphisms were investigated: TNF-308 (G→A), IL-10-1082 (G→A), IL-10-819 (C→T), IL-10-592 (C→A), IL-2 (T→G), IL-6 (G→C), TGFβ1 codon 10 (+869T→C), TGFβ1 codon 25 (+915G→C), and the TNFa, TNFd, IL-10G, IL-10R and IFNγ microsatellites. In a panel of healthy Northern European Caucasoids, the results showed that the allele frequencies of all the studied polymorphisms were consistent with those reported for other UK Caucasoid populations, but differences were observed when compared to other Oriental, African and Caucasoid groups. The polymorphisms were then investigated for their effects on cytokine production. In monocytes stimulated with LPS, no detectable differences in RNA levels between different genotype were seen. However, the TNF-308A allele was found to be associated with increased secretion of TNF protein. Furthermore, the TNFd3 microsatellite allele was associated with higher production of TNF and IL-6 from LPS-stimulated PBMCs. Cytokines play an instrumental role in controlling some of the responses that follow HSCT. In HLA-identical donors and recipients, analysis of the data showed that the TNFd4 allele was associated with aGVHD. Furthermore, several TNF microsatellite alleles were associated with patient survival including the TNFd4 allele. Cytokine polymorphisms may potentially act as markers for particular HSCT outcomes. A group of Brazilian leprosy patients and control samples were genotyped for the IFNγ microsatellite. The tuberculoid patient subgroup had a significantly different allele distribution when compared to the control group. These results indicate that the IFNγ gene polymorphism may contribute to the course of leprosy post-infection.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available