Thesis (PhD) -- University of Stellenbosch, 2001. / ENGLISH ABSTRACT: The advent of the new millennium saw the complete sequencing of the entire human genome.
Only approximately 30 000 genes, much less than was initially predicted, have been identified
to be responsible for the genetic diversity in humans. This discovery has prompted a shift in
the approach to disease research, since one gene can be involved in numerous diseases. This
phenomenon seems to be especially true for the low-density lipoprotein receptor (LDLR)
gene. Various substances beside sterols can induce transcription of the LDLR gene.
Non-communicable diseases (e.g. hypertension) are common in the developing world and
contribute significantly to mortality rates. The fmding that a promoter variant (-175 g~t) in
the LDLR gene is associated with elevated diastolic blood pressure may explain the
phenomenon of high LDL-cholesterollevels in hypertensive individuals. Studies have
demonstrated that the lowering of cholesterol, especially LDL-cholesterol, can reduce the
incidence of hypertension. The -175 g~t variant is located in a newly described cis-acting
regulatory element which contains a putative binding site for Yin Yang (YY)-l and also
demonstrates great homology to the cAMP response element (CRE) which bind the Ca2+-
dependent transcription factor, CRE binding protein (CREB). The fact that Ca2+ can induce
transcription of the LDLR gene may, at least in part, explain the association between the -
175g~t variant and elevated diastolic blood pressure.
Cholesterol is important for various processes, such as apoptosis, maintenance of cellular
membranes and immune function. The -59 c-ot mutation in repeat 2 of the LDLR gene
abolishes binding of the sterol regulatory element binding protein(SREBP) to the SRE-l site.
SREBP is proteolytically activated during apoptosis by two caspases (CPP32 and Mch3) to induce cholesterol levels. Our results imply that the -59C/T mutation, in repeat 2 of the LDLR
gene promoter, may inhibit apoptosis under normal immunological conditions.
Atherosclerosis can be considered an immunological disease, since various humoral and
cellular immune processes can be detected throughout the course of the disease. The fmding
that certain lipoproteins can protect against infection by binding and lysing of pathogens, or
competing with pathogens for cellular receptors, prompted the investigation into the potential
role of variation in the LDLR gene promoter in immune function. A significant difference in
allelic distribution was detected between asymptomatic HIY -infected subjects and fast
progressors for the -124 c-ot variant (P=O.006), shown to increase (~160%) transcriptional
activity of the LDLR gene. Of relevance to this particular study is the fact that human
herpesvirus (HHV) 6 can transactivate CD4 promoters through a partial CRE site. It has been
shown that the CREB and YYl can regulate viral and cellular promoters, and these
transcription factors can potentially bind to the LDLR promoter at the FP2 site.
The mutation enrichment in the LDLR gene promoter seen in the South African Black and
Coloured population groups can possibly provide insight into the pathogenesis of various
diseases. This could also potentially, provide novel targets for treatment, since manipulation
of cholesterol levels may affect the pathogenesis of various diseases. / AFRIKAANSE OPSOMMING: Die volledige DNA volgorde bepaling van die mensgenoom is voltooi vroeg in die nuwe
millennium. Slegs ongeveer 30 000 gene is geidentifiseer, heelwat minder as wat in die
verlede voorspel is, wat verantwoordelik is vir die genetiese diversiteit in die mens. Hierdie
ontdekking het gelei tot 'n verandering in die benadering van navorsing ten opsigte van
siektes, aangesien een geen 'n rol by verskeie siektes kan speel. Hierdie gewaarwording blyk
veral waar te wees vir die lae digtheids lipoproteien reseptor (LDLR) geen. Verskeie stimuli,
buiten sterole, kan transkripie van die LDLR geen inisieer.
Verskeie siektes soos hipertensie is algemeen in die ontwikkelende wereld, en dra by tot die
hoe mortaliteit syfers. Die bevinding dat 'n promoter variant in die LDLR geen (-175g-H)
geassosieer is met verhoogde diastoliese bloeddruk, kan moontlik verhoogde lipiedvlakke in
hipertensiewe individue verklaar. Studies het aangetoon dat die verlaging van cholesterol,
veral LDL-cholesterol, die voorkorns van hipertensie kan verlaag. Die -175 g~t variant is
gelee in 'n cis-regulerende element wat na bewering 'n bindingsetel vir die Yin Yang (YY)-l
transkripsie faktor bevat asook sterk homologie met die cAMP respons element (CRE) toon,
wat bind aan die Ca2
+_ afhanklike transkripie faktor, CRE bindings proteiene (CREB). Die feit
dat Ca2+ transkripsie van die LDLR geen kan inisieer, kan dalk tot 'n mate, 'n verklaring bied
vir die assosiasie tussen die -175 (g~t) variant en verhoogde diastoliese bloeddruk.
Cholesterol is noodsaaklik vir verskeie prosesse soos apoptose, die instandhouding van
selmembrane sowel as immuun funksies. Die -59 c-ot mutasie in die sterol regulerende
element 1 (SRE-l) van die LDLR geen vernietig binding van die sterol regulerende element
bindingsprotei'en (SREBP) aan SRE-l. SREBP word proteolities geaktiveer tydens apoptose deur twee kaspases (CPP32 en Mch3) om cholesterolvlakke te induseer. Ons resultate
impliseer dat die -59C/T mutasie, in herhaling-2 van die LDLR-geen promoter, apoptose kan
inhibeer onder normale immunologiese toestande.
Aterosklerose kan beskou word as 'n immunologiese siekte, aangesien verskeie humorale en
sellulere immuun prosesse deur die verloop van die siekte waargeneem kan word. Die feit dat
Iipoproteiene beskermend kan wees teen infeksies, deur binding en lisering van virusse of
kompeteer met patogene vir sellulere reseptore, het aanleiding gegee tot 'n ondersoek na die
potensiele rol van variasies in die promoter area van die LDLR geen in immuun funksie.
Betekenisvolle verskille in alleel verspreiding vir die -124c~t variant (P=0.006) is
waargeneem tussen asimptomatiese MIV -geinfekteerde pasiente en individue met vinnige
siekte progressie. In vitro studies het voorheen getoon dat die -124c~t 'n verhoging in LDLR
geen transkripsie (160%) tot gevolg het. Dit is noemenswaardig dat 'n vroee studie getoon het
dat die mens like herpesvirus-6 (MHV6) transaktivering van die CD4 promoters deur 'n
gedeeltelike CRE bindingsetel kan bewerkstellig. Beide CREB en YYl kan virus en sellulere
promotors reguleer, en hierdie transkripsie faktore toon bindingshomologie met die FP2
element van die LDLR promotor
Die mutasie verryking van die LDLR geen promoter soos waargeneem in Suid Afrikaanse
Swart en Kleurling populasies, kan moontlik lig werp op die patogenese van verskeie
siektetoestande. Hierdie bevindinge kan potensieel nuwe teikens vir behandeling identifiseer,
aangesien manipulasie van cholesterolvlakke 'n effek mag he op die patogenese van verskeie
siektes.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/52345 |
| Date | January 2001 |
| Creators | Scholtz, C. L.(Charlotte Latitia) |
| Contributors | Kotze, M. J., George, G., Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Interdisciplinary Health Sciences. |
| Publisher | Stellenbosch : Stellenbosch University |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | English |
| Type | Thesis |
| Format | 172 leaves : ill. |
| Rights | Stellenbosch University |
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