| Summary: | Thesis (PhD)--Stellenbosch University, 2014. === ENGLISH ABSTRACT: Tuberculosis (TB) disease results in approximately 2 million deaths annually and is the
leading cause of death due to a single infectious agent. Previous studies have indicated that
host genetics play an important role in the development of TB. This together with pathogen
and environmental factors intensifies the complexity of this disease.
The Major Histocompatibility Complex (MHC) and Leukocyte Receptor Complex (LRC)
comprise several genes which are known to be important modulators of the host immune
response. The human leukocyte antigen (HLA) class-I genes of the MHC are involved in the
presentation of pathogenic antigens on the surfaces of infected cells, while the killer cell
immunoglobulin-like receptors (KIRs) of the LRC are involved in the recognition of self and
non-self cells. Natural Killer (NK) cells through their KIRs are thus able to kill non-self cells
through recognition of the class-I molecules expressed. Additionally, HLAs and KIRs are
extremely polymorphic and differ markedly across populations of different ethnicities.
Here we studied these genes and their polymorphisms in the South African Coloured (SAC)
population to determine their involvement in susceptibility to TB, susceptibility to disease
caused by specific Mycobacterium tuberculosis subtypes, and understanding their ancestral
contribution to the SAC with regards to the development of TB.
We showed that the KIR3DS1 gene and KIR genotypes with five or more activating KIRs,
and the presence of 3DS1, protected against the development of active TB in the SAC
population. Several HLA class-I alleles were identified as susceptibility factors for TB
disease. With regards to genes of the MHC and LRC, several loci were found to alter
susceptibility to TB in the SAC population, including MDC1, BTNL2, HLA-DOA, HLA-DOB,
C6orf10, TAP2, LILRA5, NCR1, NLRP7 and the intergenic regions between HLA-C/WASF5P
and LAIR1/TTYH1. We showed that the Beijing strain occurred more frequently in individuals with multiple
disease episodes, with the HLA-B27 allele lowering the odds of having an additional episode.
Associations were identified for specific HLA types and disease caused by the Beijing, Latin
America-Mediterranean (LAM), Low-Copy Clade (LCC), and Quebec strains. HLA types
were associated with disease caused by strains from the Euro-American or East Asian
lineages, and the frequencies of these alleles in their sympatric human populations identified
potential co-evolutionary events between host and pathogen.
Finally, we showed that the SAC population is the most diverse SA population with regards
to HLA alleles and KIR genotypes, as would be expected given the admixture of the SAC.
Based on the HLA allele class-I profiles across SA populations, we noted that the Ag85BESAT-
6, Ag85B-TB10.4 and Mtb72f vaccines currently undergoing clinical trials would
have low efficacy across most SA populations. We showed that the MHC and LRC regions in
SAC healthy controls are predominantly of European ancestry, and that SAC TB cases are
more closely related to Khoisan and black SA population groups.
Our work highlights the importance of investigating both host and pathogen genetics when
studying TB disease development and that understanding the genetic ancestral contributions
to the SAC population can contribute to the identification of true and novel TB causing
variants. === AFRIKAANSE OPSOMMING: Tuberkulose (TB) is jaarliks verantwoordelik vir ongeveer 2 miljoen sterftes en is die
hoofoorsaak van dood as gevolg van „n aansteeklike siekte. Vorige navorsingstudies het
aangedui dat die genetiese samestelling van die gasheer „n beduidende rol speel in die
ontwikkeling van TB. Die kompleksiteit van hierdie siekte word vererger deur die
betrokkenheid van die gasheer genoom sowel as bakteriële en omgewings faktore.
Die Major Histocompatibility Complex (MHC) en Leukocyte Receptor Complex (LRC)
bestaan uit verskeie gene wat die gasheer immuunrespons verstel. Die human leukocyte
antigen (HLA) klas I gene van die MHC is betrokke by die aanbieding van patogeniese
antigene op die oppervlak van geïnfekteerde selle, terwyl die killer cell immunoglobulin-like
receptors (KIRs), geleë in die LRC, betrokke is by die herkenning van eie en vreemde selle.
NK selle, deur middel van hul KIRs, kan dus vreemde selle uitwis aangesien hulle die
uitgedrukte klas I molekules kan herken. Beide HLA en KIRs is hoogs polimorfies en verskil
beduidend tussen etniese groepe.
In hierdie studie is die bogenoemde gene en hul polimorfismes in die Suid Afrikaanse
Kleurling bevolking (SAC) ondersoek om vas te stel tot watter mate dit genetiese vatbaarheid
vir TB, asook vatbaarheid vir TB wat deur spesifieke Mycobacterium tuberculosis subtipes
veroorsaak word, beïnvloed. Daar is ook gepoog om te verstaan hoe die voorouerlike bydrae
van hierdie gene die SAC met betrekking tot TB vatbaarheid affekteer.
Die resultate van die studie het aangedui dat die KIR3DS1 geen en KIR genotipes met vyf of
meer aktiewe KIRs en die teenwoordigheid van 3DS1, die SAC bevolking beskerm teen die
ontwikkeling van aktiewe TB. Verskeie HLA klas I allele is geïdentifiseer as
vatbaarheidsfaktore vir TB. Talle lokusse van die MHC en LRC gene is ook as
vatbaarheidsfaktore vir TB in die SAC bevolking geïdentifiseer, insluitende MDC1, BTNL2, HLA-DOA, HLA-DOB, C6orf10, TAP2, LILRA5, NCR1, NLRP7 en die intergeniese areas
tussen HLA-C/WASF5P en LAIR1/TTYH1.
Die studie het aangedui dat die Beijing stam meer voorkom in individue wat verskeie kere
TB gehad het en dat die HLA-B27 alleel die kanse om „n verdere episode te hê, verlaag het.
Assosiasies is geïdentifiseer tussen spesifieke HLA tipes en siekte veroorsaak deur die
Beijing, LAM, LCC, en Quebec TB stamme. HLA tipes was geassosieer met siekte
veroorsaak deur TB stamme van Euro-Amerikaanse en Oos-Asiëse afkoms. Die frekwensies
van hierdie allele, in hul ooreenstemmende mensbevolkings, dui op „n potensïele koevolusionêre
gebeurtenis tussen die gasheer en patogeen.
Die studie het ook vasgestel dat die SAC populasie die mees diverse SA bevolking is met
betrekking tot die HLA allele en KIR genotipes, soos verwag sou word gegewe die gemengde
genetiese herkoms van die SAC. Gebaseer op die HLA allele klas I profiel van verskillende
SA bevolkings merk ons op dat die Ag85B-ESAT-6, Ag85B-TB10.4 en Mtb72f vaksiene,
wat huidiglik kliniese toetsing ondergaan, nie so effektief in die meeste SA bevolkings sal
wees nie. Die studie het ook bewys dat die MHC en LRC streke in gesonde SAC kontroles,
grootliks afkomstig was van „n Europese nalatenskap en dat die SAC TB gevalle meer
verwant is aan die Khoisan en swart SA bevolkings.
Hierdie studie beklemtoon die noodsaaklikheid om beide gasheer en patogeen genetika te
bestudeer wanneer die ontwikkeling van TB ondersoek word en dat die verstaan van die
genetiese voorouerlike bydrae van die SAC bevolking kan bydra tot die identifisering van
ware en nuwe TB-veroorsakende variante.
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