Philosophiae Doctor - PhD / Solute carrier transporters belonging to the major facilitator family of membrane transporter are increasingly being recognized as a possible mechanism to explain inter-individual variation in drug efficacy and response. Genetic factors are estimated to be responsible for approximately 15-30% of inter-individual variation in drug disposition and response. The aims of this study were to determine the minor allele frequencies of 78 previously identified single nucleotide polymorphisms in the pharmacogenomically relevant SLC22A1-3 and SLCO1B1 genes in the Admixed population of South Africa. Thereafter, to determine whether allele and genotype frequencies for these SNP were different from that reported for other African, Caucasian, and Asian populations. The inferred haplotypes from the genetic information possessed the potential to subsequently be used in future to design and interpret results of pharmacogenomic association studies involving these genes and their substrate drugs. Furthermore, to determine whether the Cape Admixed population harbour novel SNPs in the proximal promoter regions of SLC22A1- 3 and SLCO1B1-3 genes, that encodes hOCT1-3 and hOATP1 and hOATP3, respectively. SNaPshot™ multiplex single base mini-sequencing systems were developed and optimized for each of SLC22A1, SLC22A2, SLC22A3, and SLCO1B1 genes covering the previously identified 78 SNPs. These systems were then used to genotype the alleles of 130 healthy Cape Admixed subjects residing in Cape Town, South Africa. In addition, the proximal promoter regions of the SLC22A1-3 and SLCO1B1-3 genes of 96 of the participants were screened for novel SNPs by direct sequencing. The Cape Admixed subjects investigated displayed a lack of variation and were monomorphic for 78% of the SNPs screened. None of the SLC22A3 SNPs investigated was observed in this study. Sequencing of the proximal promoter regions of the SLC22 and SLCO genes did not reveal any novel SNPs in the 96 Cape Admixed subjects that were screened. This study highlights the fact that African populations do not have the same allele frequencies for SNPs in harmacogenomically relevant genes. Furthermore, the Cape Admixed and other African populations do not share all reduced-function variants of the SLC22A1-3 and SLCO1B1-3 genes with Caucasian and Asian populations. In addition, previously identified novel regulatory variants in SLC22A2 did not exhibit a significant effect on the ability of the promoter to drive transcription. However, it must be noted that these results were observed at 95% confidence interval, and that a 99% confidence interval the significance may increase theoretically. Additionally, it should be noted that more intensive studies are required to determine the potential effect these novel variants may well cause. This study lays the foundation for the design and interpretation of future pharmacogenomic association studies between the variant alleles of the SLC22A and SLCO genes in the Cape Admixed population, as well as optimizations for future expression, and more importantly, drug transport assays with respect to drug disposition and efficacy. / National Research Foundation (NRF) and the Medical Research Council (MRC)

Målet med projektet är att undersöka om det går att effektivisera hur man undersöker människors gener. Detta görs genom att skapa ett program i Java. Resultatet är ett program som sorterar genotypdata från 1000 Genomes Project och utvärderar nyttan av att undersöka genotyper från flera individer samtidigt.

>Magister Scientiae - MSc / The burden of non-communicable diseases (NCDs) in South Africa is predicted to increase substantially in the next decades if the necessary preventative measures are not taken. The two most common NCDs associated with rapid mortality increase are diabetes mellitus (DM) and hypertension (HTN). Both of these diseases, i.e DM and HTN, can be a result of a combination of modifiable risk factors (behavioral) and non-modifiable risk factors (genetic, physiological, and environmental). New strategies implemented to manage these diseases should include addressing both modifiable and non-modifiable risk factors for patients with NCDs. The aim of this study was to contribute to the reduction of incidence of uncontrolled T2DM among patients taking metformin as a first-line anti-diabetic drug, through the development of individualized therapy for this drug. When implemented, this could be one of the healthcare strategies to address non-modifiable risk factors for patients with T2DM as an important NCD. The first objective of the study was to explore the prevalence and risk factors of DM and HTN in South Africa, especially within the economically disadvantaged population.