Dissertation (PhD)--Stellenbosch University, 2007. / 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. / AFRIKAANSE OPSOMMING: Kandidaatgene vir die vatbaarheid vir tuberkulose en die effek van verskeie faktore op sputum
oorgangstyd was in hierdie navorsingsstudie ondersoek in die Suid-Afrikaanse Kleurlingbevolking
(SAC). Dié bevolking was ook getoets vir populasie-stratifikasie, waarvan daar geen bewyse
gevind is nie. Populasiegebaseerde pasiënt-kontrole studies was die primêre metode van analise
en verskeie genotipering metodes was gebruik.
Polimorfismes in kandidaatgene soos RANTES, CCR5, CCR2 en SDF1 was nie met die
vatbaarheid van tuberkulose geassosieer nie. Oorspronklik was daar ‘n assosiasie met die
RANTES -403 polimorfisme, maar met die genotipering van addisionele individue het die
assosiasie verdwyn. Resultate verkry vir die polimorfisme illustreer die uitdagings waaraan
assosiasie studies onderworpe is.
Die C-tipe lektiene DC-SIGN, wat gekodeer word deur CD209, en L-SIGN is belangrike
patogeen herkenningsreseptore in die aangebore immuunreaksie. Interaksies tussen beide lektiene
en Mycobacterium tuberculosis is voorheen gerapporteer. Die CD209 promoter polimorfismes, -336
en -871, was met die vatbaarheid van tuberkulose geassosieer. ‘n Haplotipe bestaande uit die
CD209 -871G en -336A allele was sterk met die kontrole groep geassosieer. Die CD209 -336A
alleel was geassosieer met ‘n toename in die DC-SIGN proteïen vlakke, wat moontlik ‘n
onderliggende rede is vir die toename in die effektiwiteit van die gasheer se fagosiete.
Vatbaarheid vir tuberkulose is onlangs toegeskryf aan die Ipr1 geen in muise. Agt polimorfismes,
insluitend 2 voorheen onbekendes, was in die mens homoloog SP110 bestudeer. Geen positiewe
beduidende assosiasie was met enige van die polimorfismes gevind nie ten spyte van die feit dat
twee van hierdie polimorfismes voorheen met tuberkulose vatbaarheid geassosieer was in
bevolkings van Wes-Afrika.
‘n Versameling van 249 TB pasiënte van ‘n longitudinale studie was beskikbaar. Dié groep was
gebruik om polimorfismes FokI, ApaI and TaqI in die vitamien D reseptor geen (VDR) te
bestudeer ten opsigte van vatbaarheid vir tuberkulose of sputum oorgangstyd sowel as ander
kliniese en demografiese faktore wat die tempo van respons op behandeling kan affekteer. In
hierdie studie was daar geen assosiasie gevind tussen die ontwikkeling van tuberkulose en die
VDR genotipes nie. Die bepaling van ‘n betroubare oorgangstyd vir beide smeer en kultuur van
die groep was moontlik. Analises was uitgevoer om te bepaal watter faktore bydrae tot vinniger
resolusie van Mycobacteria in sputum. Resultate verkry het aangedui dat die aard van die siekte
tydens diagnose voorspelbaar was van die oorgangstye van beide smeer en kultuur in die finale
modelle. Die rookstatus van individue sowel as die VDR genotipes het onafhanklik bygedrae tot
die oorgangstyd van die smeer, met ApaI ‘AA’ en TaqI ‘T’ bevattende genotipes wat ‘n vinniger
reaksie op tuberkulose behandeling voorspel het. Ter opsomming, die tyd wat dit ‘n individu op
DOTS terapie neem om na sputum negatief oor te gaan kan onafhanklik deur die VDR genotipe
voorspel word. Dit kan moontlik implikasies hê vir ander immunomodulerende terapië in die
toekoms.
Die identifisering van faktore wat bydra tot die vatbaarheid van turberkulose sal ons in staat stel
om ‘n beter begrip te hê van die immuunrespons teen tuberkulose wat moontlik kan lei tot die
ontwikkeling van akkurate behandelings en inentings.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/21524 |
| Date | 12 1900 |
| Creators | Babb, Chantal Louiza |
| Contributors | Hoal, Eileen, Van Helden, Paul, Stellenbosch University. Faculty of Health Sciences. Dept. of Biomedical Sciences. |
| Publisher | Stellenbosch : Stellenbosch University |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | English |
| Type | Thesis |
| Format | xvii, 235 leaves : ill. |
| Rights | Stellenbosch University |
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