A number of polymorphisms in the human VDR gene (located on chromosome 12q12-14) have previously been associated with TB susceptibility, of which most commonly, FokI, BsmI, ApaI and TaqI. The active metabolite of vitamin D, 1,25 dihydroxyvitamin D3, is an important immunoregulatory hormone. Its effects are exerted via the VDR, which is present on human monocytes and activated T and B-lymphocytes. Considering the role of the VDR and it specific immunological functions, including activation of monocytes, stimulation of cell-mediated immunity, suppression of lymphocyte proliferation, immunoglobulin production and cytokine synthesis, variation in the VDR genes may contribute to disease susceptibility. Hypothesis and objectives: In this study it was hypothesized that polymorphisms in the vitamin D receptor (VDR) gene influence TB susceptibility in the Venda population of South Africa. The role of VDR polymorphisms in TB susceptibility was investigated by setting the following objectives: 1. Typing of VDR gene polymorphisms (FokI, BsmI, ApaI and TaqI) in controls and TB cases as well as family samples from a Venda population of the Northern Province of South Africa. Comparing VDR allele and genotype frequencies between the Venda population and other populations as reported in the literature. 2. Analysis of possible associations in the case-control and family-based study 3. Studying Linkage disequilibrium (LD) in the case-control and the family samples. 4. Screening VDR haplotypes in the case-control and family-based study for possible association with TB. Patient and laboratory methods: VDR polymorphisms were studied in controls (n=110), TB cases (n=113) and 25 families in the Venda population inhabiting the Northern Province of South Africa. Case-control studies are vulnerable to false positive results caused by inadequate matching of the two groups. For this reason, a withinfamily association test was also implemented (the transmission disequilibrium test, TDT), as this is robust to this possible source of error. ARMS-PCR was used to type the VDR allele polymorphisms. The Statistical Package for Social Sciences (SPSSv10) was used to analyze possible association in case-controls, while TRANSMIT was used to analyze transmission of VDR alleles to affected offspring. LD between the single nucleotide polymorphisms (SNPs) of the VDR gene was investigated using the software “Graphical Overview of Linkage Disequilibrium” (GOLD) in both case-control and family studies. Possible association of TB with haplotypes comprising the VDR SNPs, ApaI and TaqI, were determined using SPSSv10 and TRANSMIT respectively for case-controls and the family based study. Results: 1. The comparative analysis indicated that the allele frequencies of the VDR SNPs related to the African American population. Genotype frequencies for FokI, BsmI and TaqI were similar to the West African population, whereas ApaI did not relate to any of the populations investigated. 2. No significant differences existed concerning the allele frequencies or genotype distribution between controls and TB cases with regard the VDR SNPs; FokI, BsmI and TaqI. The ApaI allele ‘A’ differed between cases and controls (p=0.041) but, no significant differences were obtained for genotype distribution between cases and controls for this SNP. All SNPs were in Hardy-Weinburg equilibrium except for ApaI. No differences between controls and cases were observed concerning allele presence or absence. In the family-based study, no significant difference was observed between observed and expected numbers of transmission for neither alleles nor genotypes, although, a borderline association was observed between TaqI ‘T’ allele and TB susceptibility (p=0.084). 3. LD in the case-control study was found between the VDR SNPs: BsmI and ApaI (p=0.051, D’=0.478), BsmI and TaqI (p=0.007, D’=0.222) and ApaI and TaqI (p=0.003, D’=0.479). In the family-based study, LD was only observed between ApaI and TaqI (p=0.049, D’=0.001) 4. Haplotype analysis in the case-control study indicated that no significant difference between controls and TB cases was observed. The family-based study indicated that transmission of the VDR haplotype ‘AT’ and ‘at’ differed from the expected transmission, but was of borderline significance. ‘AT’ was transmitted more than expected (P=0.090) and ‘at’ was transmitted less than expected (P=0.075), indicating that ‘AT’ may play a role in TB susceptibility and ‘at’ may play a protective role. Conclusion: The current study supports a possible role for VDR polymorphisms, ApaI (‘A’, p=0.041), or nearby yet unidentified markers in TB susceptibility in African populations (FokI-ApaI-BsmI-TaqI) (p=0.049). A larger sample size may clarify associations found to be of borderline significance. Results obtained may contribute to an improved understanding of genetic susceptibility factors in Africans. / Prof. L. Bornman
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:uj/uj:6939 |
| Date | 09 May 2008 |
| Source Sets | South African National ETD Portal |
| Detected Language | English |
| Type | Thesis |
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