Analysis of host determining factors in susceptibility to tuberculosis in the South African coloured population

De Wit, Erika (Stellenbosch : University of Stellenbosch, 2009-12)

Thesis (PhD (Biomedical Sciences. Molecular Biology and Human Genetics))--University of Stellenbosch, 2009.

Dissertation presented for the degree of Doctor of Philosophy in Medical Biochemistry at Stellenbosch University.

Thesis

ENGLISH ABSTRACT: The infectious disease tuberculosis (TB) still represents a global threat due to its devastating effect on health and the subsequent high mortality rate. Previous studies have indicated that host genetic factors are implicated in host susceptibility to TB. Since TB is a complex disease, it can be assumed that susceptibility to M. tuberculosis has multiple genetic causative factors (as well as environmental causes). The current study focussed on a number of South African Coloured (SAC) individuals, some of whom were TB cases and others controls. Population substructure was tested in the admixed SAC population as it can be a strong confounding factor for association studies. Our results using the programme STRUCTURE indicated no population substructure in the SAC population. We further investigated the population structure of the SAC group using Affymetrix 500k SNP chip data which showed that the SAC population group has 4 major ancestral components: the Khoesan, European, African and Asian (Indian). A number of candidate polymorphisms in eight genes, previously indicated to play an important role in TB susceptibility, were tested in case-control associations studies. We found statistically significant associations between IFNGR1, IL-8, IL-1Ra and NRAMP1 polymorphisms and TB susceptibility in the SAC population. It has become increasingly evident that gene-gene interactions play a far more important part in an individual’s susceptibility to a complex disease than single polymorphisms would on their own. The importance of epistasis was clearly identifiable in this study with only four associations found between the individual variants and TB susceptibility, but eight instances of statistically significant gene-gene interactions. A combined data set consisting of 106 variants constructed from our database and also used for gene-gene interaction analysis yielded numerous statistically significant interactions. The interaction between the genotype of the human host and the bacterial strain genotype was also investigated and yielded interesting results. Owing to various polymorphisms in several cytokine genes, the protein levels of the main modulators of the immune system, cytokines and chemokines, are changed in several diseases such as infectious diseases and may affect susceptibility or resistance to TB. The functional polymorphisms or haplotype patterns in some of these cytokine genes might be vital for protective immune responses and may serve as biomarkers of protection or susceptibility to TB. The present study investigated 18 cytokines including pro-inflammatory, anti-inflammatory and chemokine factors in healthy (mantoux positive or negative) children using the Linco-plex immunoassay, and investigated potential interactions. The basic research will one day contribute to personalised genetics which may benefit infectious diseases such as TB. If individuals can be identified as potentially more vulnerable, they may require different vaccination strategies, a higher index of suspicion if exposed to TB, and prophylactic treatment.

AFRIKAANSE OPSOMMING: Die infektiewe siekte tuberkulose (TB) is steeds ‘n gevaar wat die hele wêreld bedreig weens die groot impak op gesondheid en die gevolglike hoë mortaliteit. Vorige studies het bevind dat die gasheer se genetiese faktore wel betrokke mag wees by die gasheer se vatbaarheid vir TB. Aangesien TB ‘n komplekse siekte is, kan dit aanvaar word dat vatbaarheid tot M. tuberculosis veelvuldige genetiese oorsaaklike faktore (sowel as omgewingsoorsake) het. Hierdie studie het gefokus op ‘n aantal Suid-Afrikaanse Kleurling (SAC) individue, waarvan sommige TB pasiënte en ander kontroles was. Die gemengde SAC populasie is getoets vir populasie-stratifikasie, aangesien stratifikasie ‘n sterk verwarrende invloed op pasiënt-kontrole studies kan hê. Ons resultate is verkry met behulp van die program STRUCTURE en het aangedui dat daar geen populasie sub-struktuur tussen die pasiënte en kontroles was nie. Ons het ook die populasiesamestelling van die SAC groep ondersoek met data verkrygbaar van die Affymetrix 500k enkel nukleotied polimorfisme mikroskyfie. Hierdie data het getoon dat die SAC populasie uit 4 hoof voorouerlike komponente bestaan naamlik die Khoesan, Europeërs, Afrikane en Asiate (Indiërs). ‘n Aantal kandidaat polimorfismes in agt gene, wat volgens vorige studies ‘n belangrike rol in TB vatbaarheid te speel, was in hierdie pasiënt-kontrole assosiasie studie bestudeer. Ons het statistiese beduidende verwantskappe tussen IFNGR1, IL-8, IL-1Ra en NRAMP1 polimorfismes en TB vatbaarheid in die SAC populasie gevind. Dit het al hoe meer duidelik geword dat geen-geen interaksies ‘n baie belangriker rol in ‘n individu se vatbaarheid vir ‘n komplekse siekte speel as enkel polimorfismes op hul eie. Die belang van epistase kon duidelik in hierdie studie geïdentifiseer word met slegs vier assosiasies wat tussen die individuele variante en TB vatbaarheid gevind is, in vergelyking met agt statisties beduidende geen-geen interaksies. ‘n Gekombineerde datastel wat uit ons databasis saamgestel is en wat 106 variante bevat is ook in ‘n aparte geen-geen interaksie analise gebruik, wat verskeie statisties beduidende interaksies getoon het. Die interaksie tussen die menslike gasheer genotipe en die bakteriese stam genotipe is ook in hierdie studie ondersoek en het interessante resultate opgelewer. Veranderde proteïen uitdrukking van die hoofmoduleerders van die immuunsisteem, sitokine en chemokine, kom voor in verskeie siektes soos infektiewe siektes weens verskillende polimorfismes in verskeie sitokien-gene. Sulke polimorfismes kan ook vatbaarheid vir of weerstandigheid teen TB beïnvloed. Die funksionele polimorfismes of haplotipe patrone in sommige van hierdie sitokien-gene mag noodsaaklik wees vir beskermende immuunresponse en mag ook as biomerkers vir beskerming teen of vatbaarheid vir TB dien. Hierdie studie het 18 sitokiene (insluitend pro-inflammatoriese-, anti-inflammatoriese- en chemokiene faktore), sowel as potensiële interaksies in gesonde (mantoux positiewe of negatiewe) kinders, ondersoek met behulp van die Linco-plex immuno-analise. Hierdie basiese navorsing sal eendag in die toekoms bydrae tot persoonlike genetiese analises wat tot voordeel kan wees vir infektiewe siektes soos TB. Indien individue as potensieël meer vatbaar vir TB geïdentifiseer kan word, kan sulke persone ander vaksineringstrategieë sowel as voorkomende behandeling vereis.

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