Doctoral Degrees (Biochemistry)
Permanent URI for this collection
Browse
Browsing Doctoral Degrees (Biochemistry) by Author "Babb, Chantal Louiza"
Now showing 1 - 1 of 1
Results Per Page
Sort Options
- ItemIdentification of candidate genes and testing for association with tuberculosis in humans(Stellenbosch : Stellenbosch University, 2007-12) Babb, Chantal Louiza; Hoal, Eileen; Van Helden, Paul; Stellenbosch University. Faculty of Health Sciences. Dept. of Biomedical Sciences.ENGLISH ABSTRACT: This research investigated human candidate genes for susceptibility to tuberculosis and the effect of various factors on time to sputum conversion in the admixed South African Coloured (SAC) population. Population stratification was formally tested and excluded. Population based casecontrol studies were the primary analysis method with a variety of genotyping methods. Candidate polymorphisms in RANTES, CCR5, CCR2 and SDF1, were not associated with tuberculosis susceptibility. Initially the RANTES polymorphism -403 was found to be associated with tuberculosis susceptibility but after the testing of additional samples the association was lost, illustrating the challenges with association studies. The C-type lectins DC-SIGN, encoded by the gene CD209, and L-SIGN are important pathogen-recognition receptors of the human innate immune response. Both lectins have been shown to interact with Mycobacterium tuberculosis. CD209 promoter polymorphisms, -336 and - 871, were both found to be associated with tuberculosis susceptibility. The haplotype containing CD209 -871G and -336A was strongly associated with the control group. The CD209 -336A allele has been found to be associated with increased DC-SIGN expression, which may be the underlying reason for an increased efficiency of host phagocytes. Susceptibility to tuberculosis in mice has recently been attributed to the Ipr1 gene. Eight polymorphisms in the human homologue, SP110, were investigated, including two novel polymorphisms. No significant associations were found with any of the polymorphisms investigated, including two polymorphisms that were previously found to be associated with tuberculosis susceptibility in West African populations. A cohort of 249 cases from a longitudinal study of first time pulmonary tuberculosis patients was available. The cohort was used to investigate if the vitamin D receptor gene (VDR) polymorphisms FokI, ApaI and TaqI were associated with tuberculosis susceptibility or time to sputum conversion, and to investigate other clinical and demographic factors affecting the rate of response to treatment. No association between the VDR genotype and tuberculosis was found in the case-control study. The cohort allowed for a reliable conversion time to be determined for smear (n=220) and culture (n=222). Analysis was carried out to determine which factors, including VDR FokI, ApaI, and TaqI genotypes, contribute to faster mycobacterial resolution in sputum. This was done by survival curves and Cox regression models. The results indicate that the extent of disease at diagnosis was predictive of both smear and culture conversion times in the final models. Smoking status and VDR genotype contributed independently to smear conversion time, with ApaI ‘AA’ and TaqI ‘T’ containing genotypes being predictive of a faster response to tuberculosis therapy. We can conclude that the time taken for an individual to convert to sputum negativity while on DOTS therapy, can be independently predicted by the VDR genotype. This may have implications for future immunomodulatory therapies. Identifying what contributes to susceptibility to tuberculosis will provide us with a better understanding of the human immune response to tuberculosis which may lead to the development of accurately targeted therapeutics and vaccines.