Thesis (PhD)--Stellenbosch University, 2003. / ENGLISH ABSTRACT: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system.
Current knowledge suggests that MS is associated with autoimmunity and that infectious
agents and hereditary factors may be involved. The demonstration of a higher
recurrence risk of MS in families (4-5%) compared with the general population (0.1%)
provides strong evidence for a genetic basis. Extensive analyses of the entire human
genome to identify new genes that may underlie MS have indicated that several genes
may contribute to disease susceptibility, but these remain largely unidentified.
In this study candidate genes involved in iron metabolism and immunology have been
analysed for the first time within the context of both autoimmune and infectious disease
susceptibility, in order to investigate the role of genetic and viral factors implicated in the
pathogenesis of MS.
The Z-DNA forming repeat polymorphism in the promoter region of the solute carrier
family 11 (proton-coupled divalent ion transporters) member 1 (SLC11A1) gene was
found to be significantly associated with MS (P<0.01) in the genetically homogeneous
Afrikaner population of South Africa, but not in the German and French populations
using a case-control study and transmission linkage disequilibrium approach,
respectively. However, significant differences were observed in genotype distribution
between German MS patients with a primary- and secondary progressive disease
course (P<0.05), and between the German patients with relapsing remitting and primary
progressive MS (P<0.05). These findings provide further evidence that the SLC11A1
gene is associated with MS, most likely due to its role in iron homeostasis.
In order to investigate the influence of viruses in the apparent multi-step aetiology of MS,
serum and peripheral blood mononuclear cells (PBMCs) of MS patients, close relatives
and unrelated controls were screened for the presence of MS-associated retrovirus
(MSRV) and two herpes virus (HHV-6 and EBV) sequences. Detection of the pol gene
expression of MSRV in the serum RNA of 69% of South African MS patients and in 70% of their unaffected close relatives, whilst absent in the serum of 39 unrelated healthy
control individuals (P<0.001), indicated that virus infections affect the population risk but
not the familial risk in MS. HHV-6 sequences were also present at a significantly lower
frequency (P<0.04) in the PBMCs of unrelated controls (5%) compared to MS patients
(22.5%).
A point mutation (77C^G) in the gene encoding protein-tyrosine phosphatase, receptortype
C (PTPRC), which is essential for activation of T and B cells, was found to be
associated with MS in the German population. Analysis of the Afrikaner and German
study populations included in our study did not indicate a causative role for the PTPRC
gene in MS. However, it seems likely that this mutation may contribute to disease
expression, since in one of the South African families with two MS affected sibs, the
most severely affected sister was heterozygous for the 77C-»G mutation. The PTPRC
mutation may therefore be of significance in disease prognosis.
The multidisciplinary study approach has led to a stepwise accumulation of scientific
information, which forever changed our understanding of the disease process underlying
MS. / AFRIKAANSE OPSOMMING: Veelvoudige sklerose (VS) is ‘n kroniese inflammatoriese siekte van die sentrale
senuweestelsel. Oor die algemeen word aanvaar dat VS geassosieerd is met
outoimmuniteit en dat infektiewe agente en oorerflike faktore ’n rol speel. Die hoër
herhalingsrisiko van VS in families (4-5%) in vergelyking met die voorkoms in die
algemene populasie (0.1%) dui op 'n genetiese basis. Alhoewel volledige analise van
die mensgenoom om gene onderliggend aan VS te identifiseer aangedui het dat
verskeie gene waarskynlik bydra tot vatbaarheid vir die siekte, is die aard van die gene
wat betrokke is grootliks onbekend.
In hierdie studie is kandidaatgene betrokke by ystermetabolisme en immunulogie vir die
eerste keer geanaliseer binne die konteks van beide outoimmuun en infektiewe siekte
vatbaarheid, ten einde die rol van genetiese en virale faktore in die patogenese van VS
te ondersoek.
Die Z-DNS herhalingsvolgorde polimorfisme in die promotor area van die SLC11A1
geen was betekenisvol geassosieerd met VS (P<0.01) in die geneties homogene
Afrikaner populasie van Suid-Afrika. ’n Soortgelyke assosiasie kon egter nie aangetoon
word in die Duitse en Franse populasies deur gebruik te maak van onderskeidelik ‘n
gevalle-kontrole studie en transmissie-koppelings-disekwilibrium benadering nie.
Betekenisvolle verskille in die genotipe verspreiding is egter tussen Duitse VS pasiente
met ‘n sekonder- en primer progressiewe verloop van die siekte (P<0.05), en tussen die
Duitse pasiente met terugvallende en primere progressiewe VS aangetoon (P<0.05).
Hierdie bevinding verskaf verdere bewyse dat die SLC11A1 geen geassosieerd is met
VS, heel waarskynlik weens die rol van die geen in yster-homeostase.
Ten einde die invloed van virusse in die etiologie van VS te ondersoek is serum en
witbloedselle van VS pasiente, naby-verwante familielede en nie-verwante kontroles
getoets vir die teenwoordigheid van die VS-geassosieerde retrovirus (MSRV) en twee
herpesvirus (HHV-6 en EBV) geenvolgordes. Die pol geen uitdrukking van MSRV was teenwoordig in die serum RNA van 69% van die Suid-Afrikaanse VS pasiente en in 70%
van hul ongeaffekteerde naby-verwante familielede, terwyl dit afwesig was in 39 nieverwante
kontrole individue (P<0.001). Dit dui daarop dat virusse waarskynlik die risiko
vir VS meer in die populasie verhoog as in families. HHV-6 was ook teenwoordig teen ‘n
beduidende laer frekwensie (P<0.04) in nie-verwante kontroles (5%) in vergeleke met
VS pasiente.
‘n Puntmutasie (77C-G) in die geen wat kodeer vir die proteien tirosien fosfatase
reseptor tipe C (PTPRC), wat belangrik is vir aktivering van T- en B-helperselle, is
vroeer gevind om geassosieerd te wees met VS in die Duitse populasie. Analise van die
Afrikaner en Duitse populasies in ons studie het egter geen bewyse gelewer dat die
PTPRC geen ‘n rol speel in VS nie. Dit egter is moontlik dat hierdie mutasie bydra tot die
uitdrukking van VS, aangesien die mees geaffekteerde VS pasient in een van die Suid-
Afrikaanse families met twee geaffekteerde susters positief getoets het vir die mutasie.
Die mutasie mag dus van belang wees in die prognose van VS.
Die multidissiplinere studie-benadering en stapsgewyse insameling van wetenskaplike
inligting het gelei tot ’n nuwe perspektief ten opsigte van die siekteproses onderliggend
aan VS.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/53252 |
| Date | 03 1900 |
| Creators | De Villiers, J. N. P. |
| Contributors | Kotze, M. J., Warnich, L., de Jong, G., Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Molecular Biology and Human Genetics. |
| Publisher | Stellenbosch : Stellenbosch University |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | English |
| Type | Thesis |
| Format | 118 p. : ill. |
| Rights | Stellenbosch University |
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