Thesis (MSc)--Stellenbosch University, 2003. / ENGLISH ABSTRACT: With knowledge of the human genome increasing constantly we are continually faced
with new and potentially groundbreaking methods for managing, treating and/or
identifying diseases and predisposition to diseases and conditions at a genetic level.
The human cytochrome P450 (CYP) super-family of genes code for enzymes that can
participate in metabolism of drugs and foreign chemicals and in steroid synthesis and
metabolism. Mutations in these genes may contribute to clinically relevant diseases.
In this study, the effects of mutations within four CYP genes were evaluated in two
South African disease groups - variegate porphyria and breast cancer.
Variegate porphyria (VP) has an unusually high incidence in South Africa due to the
R59W founder mutation in the protoporphyrinogen oxidase (PPOX) gene that causes
a disruption in the haem biosynthetic pathway. VP presents with variable clinical
symptoms and has a relatively low penetrance. It is expected that environmental
factors and modifier genes play a role in the clinical expression of VP. CYP genes
are implicated as candidate modifier genes for the expression of VP due to the
function they have in metabolising many drugs contraindicated in porphyria patients,
and the necessity of haem binding to the apoprotein to produce a functional CYP
enzyme. This is the first study to investigate CYPs as possible modifier genes for VP
clinical expression. Six CYP polymorphisms (CYPIAlml, CYPIAlm2, CYPIA2 -
734 C>A, CYPIBI 8372 A>C, CYP2D6*3, CYP2D6*4), associated with four CYP
loci, were genotyped in a VP population and a suitable control population. The
results observed are suggestive of CYPIAlml and CYPIBI playing a role as
modifiers for the clinical expression of VP as they were significantly associated
(P<O.05) with the presence ofVP related symptoms.
Breast cancer is one of the leading causes of death in women due to cancer. It is
believed that breast cancer may be the result of co-participation between common
DNA alterations and environmental exposures. Polymorphisms in enzymes involved
with the metabolism of environmental exposures, such as the cytochrome P450
enzymes, are therefore expected to play an aetiological role in breast cancer. Two
groups of South African breast cancer patients (Caucasian and of mixed ancestry) and population-matched controls were genotyped for four CYP polymorphisms
(CYPIAlml, CYPIAlm2, CYPIA2 -734 C>A and CYPIBI 8372 A>C). This
represents the first investigation of the potential role of CYPs as breast cancer risk
modifiers in the two South African populations. Significant differences were
observed (P<O.003) in genotype and allele frequencies between the breast cancer
patients and controls for the CYPIBI 8372 A>C polymorphism in the population of
mixed ancestry. Vast differences in allele frequencies were also observed between
the two groups of breast cancer populations. These results emphasize the importance
of population-based risk assessment when genetic testing and counselling for complex
disease susceptibility is offered.
The results of this study provide the first evidence suggesting a role for CYPs in
modifying the clinical expression of VP and in acting as risk factors for developing
breast cancer in a South African population. / AFRIKAANSE OPSOMMING: Met die konstante toename van kennis oor die mensgenoom kom ons voortdurend te
staan voor nuwe metodes vir die beheer, behandeling en/of identifikasie van siektes
en vatbaarheid vir siektes op 'n genetiese vlak. Die mens sitochroom P450 geensuperfamilie
kodeer vir ensieme betrokke in die metabolisme van medisyne en ander
chemiese stowwe en steroïed-sintese en -metabolisme. Mutasies in hierdie gene kan
'n bydrae lewer tot kliniese relevante siektes. In hierdie studie is die effek van
mutasies in vier sitochroom gene bestudeer in twee Suid-Afrikaanse siekte groepe,
variegate porfirie en borskanker.
Variegate porfirie (VP) het 'n besonderse hoë frekwensie in Suid-Afrika as gevolg
van die R59W stigter-mutasie in die protoporfirinogeen oksidase (PPOX) geen.
Hierdie mutasie lei tot 'n versteuring in die heem biosintese padweg. VP presenteer
met variërende kliniese simptome en het 'n betreklike lae penetrasie. Daar word
vermoed dat omgewingsfaktore en kandidaat modifiserende gene 'n rol speel in die
kliniese beeld van VP. Sitochroom P450 gene is geïdentifiseer as kandidaat
modifiserende gene as gevolg van hulle rol in die metabolisme van verbode medikasie
vir porfirie pasiënte, asook die binding van heem aan die apoproteïen wat noodsaaklik
is vir die produksie van funksionele sitochroom P450 ensiem. Hierdie is die eerste
studie wat sitochroom P450 gene as moontlike modifiserende gene vir die kliniese
uitdrukking van VP ondersoek. Ses sitochroom P450 polimorfismes (CYPIAlml,
CYPIAlm2, CYPIA2 -734 C>A, CYPIBI 8372 A>C, CYP2D6*3, CYP2D6*4) is
ondersoek in beide 'n VP populasie en 'n geskikte kontrole populasie. Die resultate
suggereer 'n rol vir CYPIAlml en CYPIBI in die modifisering van die kliniese
uitdrukking van VP aangesien hulle betekenisvolle assosiasie (P<O.05) met die
voorkoms van VP-verwante simptome getoon het.
Borskanker IS een van die vernaamste oorsake van kankersterftes onder vroue.
Borskanker IS waarskynlik die resultaat van interaksie tussen algemene DNSveranderinge
en omgewings-blootstelling. Daar word dus verwag dat polimorfismes
in ensieme betrokke by die metabolisme van omgewingselemente, soos byvoorbeeld
die sitochroom P450 ensieme, 'n etiolgiese rol in borskanker sal speel. Die genotipes van twee groepe Suid-Afrikaanse borskanker lyers (Kaukasiërs en van gemengde
herkoms) en populasie-passende kontroles is bepaal vir vier sitochroom P450
polimorfismes (CYPIAlml, CYPIAlm2, CYPIA2 -734 C>A, CYPIBI 8372 A>C).
Hierdie studie verteenwordig die eerste ondersoek na die potensiële rol van
sitochroom P450s as risiko-modifiserende faktore vir borskanker in die twee
populasies. Betekenisvolle verskille (P<O.003) in genotipe en allele frekwensies is
waargeneem tussen die borskanker lyers en kontroles vir die CYPIBI 8372 A>C
polimorfisme in die gemengde herkoms populasie. Beduidende verskille in alleel
frekwensies is ook waargeneem tussen die twee borskanker populasies. Hierdie
resultate beklemtoon die belangrikheid van populasie gebaseerde risiko-beraming
wanneer genetiese toetse en voorligting vir komplekse siekte-vatbaarheid aangebied
word.
Die resultate van hierdie studie bied die eerste getuienis dat sitochroom P450s 'n rol
kan speel in die modifisering van die kliniese beeld van VP en ook kan optree as as
risiko faktore vir die ontwikkeling van borskanker in 'n Suid-Afrikaanse populasie.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/53345 |
| Date | 12 1900 |
| Creators | Gerber, Jaclyn |
| Contributors | Warnich, L., Kotze, M. J., Stellenbosch University. Faculty of Science. Dept. of Microbiology. |
| Publisher | Stellenbosch : Stellenbosch University |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | Unknown |
| Type | Thesis |
| Format | [xxi], 120 p. : ill. |
| Rights | Stellenbosch University |
Page generated in 0.0028 seconds