Pharmacogenomics of solute carrier transporter genes in the Xhosa population
Jacobs, Clifford Winston
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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 pharmacogenetically relevant SLC22A1-3 and SLC47A1 genes in the indigenous African population of South Africa. Secondly, to determine whether allele and genotype frequencies for these SNP were different from that reported for other African, Caucasian, and Asian populations. Thirdly, to infer haplotypes from the genetic information which can potentially be used in future to design and interpret results of pharmacogenetics association studies involving these genes and their substrate drugs. Finally, to determine whether the Xhosa population harbour novel SNPs in the SLC22A2 gene, that encodes the kidney-specific hOCT2. SNaPshot™ multiplex single base minisequencing systems were developed and optimized for each of SLC22A1, SLC22A2, SLC22A3, and SLC47A1 covering the previously identified 78 SNPs. These systems were then used to genotype the alleles of 148 healthy Xhosa subjects residing in Cape Town, South Africa. In addition, the proximal promoter region and all 11 exons and flanking regions of the SLC22A2 gene of 96 of the participants were screened for novel SNPs by direct sequencing. The Xhosa subjects investigated lacked heterozygosity and were monomorphic for 91% of the SNPs screened. None of the SLC22A3 and SLC47A1 SNPs investigated was observed in this study. Sequencing of the SLC22A2 gene revealed 28 SNPs, including seven novel polymorphic sites, in the 96 Xhosa subjects that were screened. The minor allele frequencies of the seven previously identified variant SNPs observed in this study were different compared to that observed for American and European Caucasian, and Asian populations. Moreover, the allele frequencies for these SNPs differed amongst African populations themselves. Eight and seven haplotypes were inferred for SLC22A1 and SLC22A2, respectively, for the Xhosa population from the information gathered with SNaPshot™ genotyping. This study highlights the fact that African populations do not have the same allele frequencies for SNPs in pharmacogenetically relevant genes. Furthermore, the Xhosa and other African populations do not share all reduced function variants of the SLC22A1-3 and SLC47A1 genes with Caucasian and Asian populations. Moreover, this study has demonstrated that the Xhosa population harbours novel and rare genetic polymorphisms in the key pharmacogene SLC22A2. This study lays the foundation for the design and interpretation of future pharmacogenetic association studies between the variant alleles of the SLC22A1-3 and SLC47A1 genes in the Xhosa population and drug disposition and efficacy.