Thesis (MScMedSc)--Stellenbosch University, 2012. / Bibliography / ENGLISH ABSTRACT: The communicable disease tuberculosis (TB) is responsible for millions of deaths each year, on a
global scale. At present the contribution of host genetics in TB is generally accepted and, together
with environmental aspects (e.g. nutrition and crowding) and the causative bacterium,
Mycobacterium tuberculosis (M. tuberculosis); it will possibly have a hand in the outcome of
disease. Clearly, TB is a multifaceted disease and the repercussions for studying genetic
susceptibility are that many genes will potentially be implicated.
To date a variety of genes such as NRAMP1 and HLA have been implicated in influencing the host
response to TB, albeit with varying effects in different populations. Some of the more recently
implicated genes are the pattern recognition receptors, the Toll-like receptors (TLRs). Genetic
variation in theses genes has been associated with a myriad of different diseases, including those of
an infectious nature, such as TB. In the case of TB, TLR2 is the most prominent candidate with
TLR8 and 9 more recently implicated. One of the more well known genes implicated with TB is the
vitamin D receptor (VDR), as the antimicrobial gene cathelicidin (CAMP), one of the most
important agents of mycobacterial killing, has a VDR response element in its promoter. TLR2, VDR
and CAMP are all connected in a complex pathway essential for the host defence against M.
tuberculosis.
Nine single nucleotide polymorphisms (SNPs) in three TLR genes (TLR2,8 & 9) were investigated
via a case-control approach to determine their potential role in human genetic susceptiblity to TB in
the Coloured population of South Africa. The effect of the VDR polymorphism Cdx2 on the
expression of cathelicidin mRNA and protein expression was also investigated.
Three genes were found to contribute significantly to genetic host susceptibility in the Coloured
population of South Africa. An allelic association (p = 0.031) was observed for the TLR8 (located
on the X-chromosome) SNP rs3761624, with the A-allele being more prominent in females. Four
haplotypes of TLR8 were found to be significantly linked to TB susceptibility with the three SNP
haplotype rs3761624-rs3764879-rs3764880, specifically the allelic combination of G/C/A [p =
0.004, OR = 2.67(95% CI: 1.90-3.74)], showing a marked association (p = 0.001). The TLR9 introexon2
boundary SNP rs352139 was significantly associated with TB susceptiblity on a genotypic (P
= 0.02) and allelic scale [p = 0.05, OR=0.70; (95% CI: 0.55–0.90)], with the T allele more frequent in controls. The TLR9 two SNP haplotype consisting of rs5743836 and rs352139 was linked (p =
0.037) to TB susceptibility, specifically the combination of the alleles A/T [p = 0.013, OR=0.71;
(95% CI: 0.55–0.92)]. No gene-gene interaction between TLR2, TLR8 and TLR9 was observed. No
significant conclusions could be drawn from the analysis of the mRNA and protein expression of
CAMP in samples harbouring the different genotypes of the VDR polymorphism Cdx2.
Genetic variations in the TLR8 and 9 genes were identified as potential factors that influence
genetic host susceptibility to tuberculosis in the Coloured population of South Africa. / AFRIKAANSE OPSOMMING: Die oordragbare siekte tuberkulose (TB) is elke jaar verantwoordelik vir miljoene sterftes
wêreldwyd. Die invloed van die gasheer genoom op TB vatbaarheid word huidiglik aanvaar,
tesame met die invloed van omgewingsfaktore (dieet, oorbevolking ens.) en die bakterium
Mycobacterium tuberculosis (M. tuberculosis). Dit is duidelik dat TB ‘n veelvlakkigesiekte is wat
beïnvloed sal word deur ‘n menigte verskillende gene.
‘n Verskeidenheid gene is al betrek by TB genetiese vatbaarheid, onder andere NRAMP1 en HLA,
hoewel hul effekte in uiteenlopende bevolkings verskil. Sommige van die onlangse gene wat betrek
is in TB genetiese vatbaarheid is die Toll-like reseptore (TLRs). Genetiese variasie in hierdie gene
is geassosieer met ‘n wye verskeidenheid van siektes, insluitend aansteeklik van aard, onder andere
TB. In die geval van TB speel TLR2 ‘n prominente rol, terwyl TLR8 en TLR9 meer onlangs
geïmpliseer is. Een van die meer bestudeerde TB vatbaarheidsgene is die vitamiene D reseptor
geen (VDR). VDR is direk betrokke in die uitdrukking van die anti-mikrobiale geen cathelicidin
(CAMP),’n integrale komponent in die vernietiging van mikobakterieë. Die CAMP geen het ‘n
VDR respons-element in sy promotor. Die TLR2, VDR en CAMP gene word verbind deur ‘n
komplekse netwerk wat integraal is tot die liggaam se vermoë om TB af te weer.
Nege enkel nukleotied polimorfismes (ENPs) in drie gene (TLR2,8 & 9) is vir hierdie studie
ondersoek, deur gebruik te maak van ‘n pasiënt-kontrole assosiasiestudies, om te bepaal watter rol
hul speel in genetiese vatbaarheid vir TB in die Kleurling bevoling van Suid-Afrika, al dan nie. Die
invloed van die VDR polimorfisme Cdx2 op die uitdrukking van die mRNS (boodskapper
ribonukleïensuur) en proteïen van die geen CAMP is ook ondersoek.
Ons het gevind dat drie gene beduidend bygedra het tot genetiese vatbaarheid vir TB in die
Kleurling populasie. ‘n Alleel verwante assosiasie (p = 0.031) was gevind vir die TLR8 SNP
rs3761624, waar die A-alleel meer algemeen was in vroue. Vier haplotipes vir TLR8 het
beduidende assosiasies met TB vatbaarheid getoon. Die drie SNP haplotipe rs3761624-rs3764879-
rs3764880, spesifiek die alleel kombinasie C/G/A [p = 0.004, OR = 2.67(95% CI: 1.90-3.74)] het
sterk assosiasie (p = 0.001) met TB getoon. Die TLR9 intron-ekson2 grens SNP, rs352139 het
beduidende assosiasie met TB getoon op ‘n genotipiese (p = 0.02) sowel as alleliese skaal [p =
0.05, OR=0.70; (95% CI: 0.55–0.90)], met die T alleel meer algemeen in kontroles. Die twee SNP haplotipe bestaande uit rs5743836 en rs352139 het TB vatbaarheid beïnvloed (p = 0.037), spesifiek
die alleliese kombinasie van A/T [p = 0.013, OR=0.71; (95% CI: 0.55–0.92)]. Geen
noemenswaardige interaksies tussen TLR2, 8 en 9 is gevind nie. So ook is geen beduidende
resultate gevind vir die effek van die VDR SNP Cdx2 op die uitdrukking van CAMP mRNS en
proteïen nie.
Genetiese variasie in die TLR8 en 9 gene is geïdentifiseer as moontlike faktore wat gasheer
genetiese vatbaarheid vir TB in die Kleurlingbevolking van Suid-Afrika beïnvloed. / WW Roome Trust
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/20390 |
| Date | 03 1900 |
| Creators | Lucas, Lance Andrew |
| Contributors | Hoal, Eileen, Moller, Marlo, Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Science. Division of Molecular Biology and Human Genetics. |
| Publisher | Stellenbosch : Stellenbosch University |
| Source Sets | South African National ETD Portal |
| Language | en_ZA, English |
| Detected Language | English |
| Type | Thesis |
| Format | xii, 153 p. : col. ill. |
| Rights | Stellenbosch University |
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