Human genetic susceptibility to tuberculosis : the investigation of candidate genes influencing interferon gamma levels and other candidate genes affecting immunological pathways
| Autor: | Moller, Marlo |
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| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: | |
| Druh dokumentu: | Diplomová práce |
| Popis: | Thesis (PhD (Biomedical Sciences. Molecular Biology and Human Genetics))--University of Stellenbosch, 2007. The infectious disease tuberculosis (TB) is one of the leading causes of death worldwide. The idea that infectious diseases are the most important driving force in natural selection and that they sustain frequent polymorphisms in the human genome was formally suggested by Haldane in 1949. This hypothesis implicated the human genetic component in the response to infectious disease. Today the involvement of host genetics in TB has been proven unequivocally and, together with environmental factors (e.g. nutrition and crowding) and the causative bacterium, Mycobacterium tuberculosis (M.tuberculosis), may influence the outcome of disease. As is evident, TB is a complex disease and the implication for studying genetic susceptibility is that a number of genes will be involved. Interferon gamma (IFN-7) is the major macrophage-activating cytokine during infection with M.tuberculosis and its role has been well established in animal models and in humans. This cytokine is produced by activated T helper 1 (Th1) cells. These Th1 responses can best deal with intracellular pathogens such as M.tuberculosis. We selected twelve candidate genes based on the hypothesis that genes which regulate the production of IFN-7 may influence TB susceptibility. We also selected polymorphisms from 27 other candidate genes, which may affect immunological pathways involved in TB, to investigate as susceptibility factors based on the following hypotheses: 1) granulomatous diseases can share susceptibility genes; 2) gene expression studies done by DNA-array analysis experiments may reveal TB susceptibility genes; 3) genomewide linkage studies in TB can determine susceptibility loci and genes in this region are possibly susceptibility factors; and 4) functional susceptibility polymorphisms in genes involved in immune-mediated diseases other than TB may contribute to susceptibility to TB. This research tested the association of 136 genetic polymorphisms in 39 potentially important genes with TB in the South African Coloured population. Well-designed case-control association studies were used and we attempted to replicate these findings in an independent sample set using family-based case-control designs (transmission disequilibrium tests (TDTs)). In addition, haplotypes and linkage disequilibrium (LD) in the candidate genes were also investigated. During the case-control analyses we found significant associations for 6 single nucleotide polymorphisms (SNPs) in the following genes: SH2 domain protein 1A, tolllike receptor 2, class II major histocompatibility complex transactivator, interleukin 1 receptor antagonist, runt-related transcription factor 1 and tumour necrosis factor superfamily, member 1B. Discrepant results were obtained during the TDT analyses. The number of families available was small and for this reason we cannot conclude that the case-control results were spurious. We also tested the association of haplotypes with TB. Haplotypes in the interleukin 12, beta (IL12B) and toll-like receptor 4 genes were nominally associated with TB in both the case-control and TDT analyses. We observed strong LD for the genes in the South African Coloured population. In total 17 novel SNPs were identified and one novel allele was found for a microsatellite in IL12B. This research contributes to the increasing amount of information available on genes involved in TB susceptibility, which in the future may help to predict high risk individuals. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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