| Summary: | This dissertation brings to the fore the “Characterization of the SULT1A1 polymorphism in a
South Africa Tswana population group.” The primary experimental group studied came from
South African homogeneous Tswana individuals who participated voluntarily in an ongoing
large-scale epidemiological Prospective Urban and Rural Epidemiological (PURE) study the
North-West University (Potchefstroom Campus) participates in, as one of the 16 low- middleand
high-income countries across the world.
The primary aspect investigated was the comprehensive profile of the single nucleotide
polymorphism (SNP) and copy number variation (CNP) of the SULT1A1 gene. Using the PCRbased
RFLP method, SULT1A1 genotypes, and allele frequency distributions in an
experimental group of 1 867 individuals were determined. According to the literature this is by
far the largest and most homogeneous group from which such information has been acquired to
date. The SULT1A1*1, SULT1A1*1/*2 and SULT1A1*2 genotypes were found to be present at
a percentage of 43.76, 47.12 and 9.11 respectively. In comparison to similar studies in other
population groups, results from this study indicate that there are ethnic differences in the
SULT1A1 genotypes incidence. Asian group differs from Caucasian and Tswana groups
because of its exceptionally high prevalence of individuals with the SULT1A1*1 genotype and a
very low incidence of the SULT1A1*2 genotype. The SULT1A1*1 genotype profiles of
Caucasian and Tswana groups were comparable, but notable differences were observed for the
SULT1A1*2 genotype.
Using a quantitative multiplex PCR method for the CNV study, the numbers of copies of the
SULT1A1 gene in the Tswana population were determined, and the results showed 1 to ~5
copies: only 0.65% of the subjects had a single copy, whereas 59.69% of the subjects had 3 or
more copies. This result shows a significant discrepancy between the Caucasian-American
samples, which showed that only 26% from that group had more than three copies. However,
there is a significant relationship with the African-American population, which presented 63%
with 3 or more copies. This finding confirms results from a much smaller African-American
study, and suggests a possible genetic link between the African Tswana and the heritage of the
African-Americans. These findings were submitted for publication to the South African Journal
of Science, as that journal specializes in publication of new knowledge that has a regional focus
on Africa. Simultaneous phenotypic consequences of the SNP and CNP of the SULT1A1 gene, as well as
the thermo-stable and thermo-labile forms of the sulfotransferases were determined. For this,
the formation of [35S]-4-nitrophenyl sulphate from 4-nitrophenol and [35S]-3’-phosphoadenosine-
5’-phosphosulfate ([35S]-PAPS) in platelet homogenates were measured, with the data
normalized to a common platelet count. This investigation required fresh blood for enzyme
activity. These samples came from 98 Caucasian subjects who voluntarily participated in this
part of the study. The experimental data presented a unique challenge to develop a statistical
model to accommodate the complexity of the distribution of the data in the phenotype and
genotype components, which could be achieved by the development of a mixed model. The
model indicated that product formation increased through increasing copy number, but did not
differ for SULT1A1*1 and SULT1A1*1/*2. However, the rate of increase in product for the
thermo-stable forms of the SULTs was greater than that of thermo-labile forms. In contrast, copy
number effect for SULT1A1*2 differed considerably from that of the other two genotypes. Since
genotype is also a significant factor, it was concluded from Tukey post-hoc tests that the
population group means for product formation differ significantly (for all levels). These results
are presently being prepared for publication in an accredited international journal.
Finally, perturbations in 23 biochemical parameters measured in the PURE study were
analyzed as a function of the SULT1A1 SNP and CNP were evaluated. No group separation in
this regard could be found. It could be shown however, that sulfonation of the iodothyronines,
which are endogenous substrates for the SULTs, was influenced by the SULT1A1 genotype.
The relative concentrations in plasma of the sulphonated iodothyronines may be expressed as
T2S > T3S >> T4S, which coincides with the substrate preference of the SULT1A1 enzymes.
This observation may, however, only be qualitatively interpreted as (1) the targeted
metabolomics mass spectrometric method used for the quantitative analysis of these
substances needs further development, and (2) the influence of deiodonation was not taken into
account in these studies. In conclusion, three perspectives are given at the end of the thesis
which might be considered for further investigations. === Thesis (Ph.D. (Biochemistry))--North-West University, Potchefstroom Campus, 2010.
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