Abstract
Fetal alcohol syndrome (FAS) is a common cause of mental retardation and is
attributable to the teratogenic effects of alcohol exposure in utero in individuals with
genetic susceptibility. The Coloured communities from the Western and Northern Cape
regions have some of the highest recorded incidence rates (~70 affected children per 1000
live births) in the world.
The candidate genes selected for this study belong to the family of alcohol
dehydrogenase genes that code for enzymes which metabolise alcohol. The ADH1B and
ADH1C genes have previously been examined in the Western Cape Coloured community
and the enzyme encoded by the allele ADH1B*2 was significantly associated with
protection against the development of FAS. ADH4, a new candidate gene, was selected
due to its role in both the alcohol and retinol metabolic pathways.
A case-control genetic association study was performed to examine the potential roles of
the ADH1B, ADH1C and ADH4 genes in the etiology of FAS in two Coloured
populations from the Northern and Western Cape. Single nucleotide polymorphisms
found within the candidate genes were typed by PCR-based methods in samples from the
FAS children, their mothers and controls.
Significant associations were observed in the Western Cape cohort but were not
replicated in the Northern Cape. Allelic association tests revealed that ADH1B*2 may be
a protective marker as it occurred more commonly in the controls than the mothers (p=
0.038). The alleles of the polymorphic variant, ADH4.8, have been shown to influence
the promoter activity of ADH4 (the ‘A’ allele has been shown to increase the activity of
the promoter when compared to the ‘C’ allele as the same position). The alleles of this
polymorphic marker were significantly associated with the risk for FAS. The ‘A’ allele
was shown to occur more commonly in the mothers and FAS-affected children (p= 0.002
and 0.035 respectively) when compared to the controls, suggesting a role in disease
susceptibility while the ‘C’ allele was shown to occur more commonly in the controls. Itwas also observed that ADH1B and ADH4.8 when examined together in a haplotype
demonstrated an association with susceptibility to the disease. While the 2-C haplotype
(ADH1B-ADH4.8) was shown to be associated with protection against the development
of FAS, the 1-A haplotype was associated with increased susceptibility. The results
suggest that mothers with the common ADH1B*1 allele and presumably a normal
ADH1B function but an increased level of ADH4 (allele ‘A’) as a result of the promoter
mutation, will, when the blood alcohol concentration is high, have an increased risk of
having a child with FAS. Conversely when the mothers have a faster alcohol
metabolising rate due to the allele ADH1B*2 and normal levels of ADH4 protein (allele
‘C’), the circulating alcohol in the blood is removed efficiently resulting in maternal
protection against developing the disease.
This study has also highlighted the genetic diversity within individuals of the South
African Coloured population. Haplotype analysis and logistic regression revealed that the
Western and Northern Cape Coloured communities are genetically different and as a
result, the samples could not be pooled for analysis. Although the two groups of controls
were genetically diverse, haplotype analysis revealed that the sample of mothers and
FAS-affected children were not statistically different between the provinces thus possibly
suggesting a similar genetic etiology for the disease. The results from this study suggest
that the ADH genes do play a role in the pathogenesis of FAS.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/4483 |
| Date | 21 February 2008 |
| Creators | Naidoo, Dhamari |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 47931 bytes, 1287617 bytes, application/pdf, application/pdf, application/pdf, application/pdf |
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