Promoter haplotype structure of solute carrier 22 member 2 (SLC22A2) in the Xhosa population of South Africa and their differential effect on gene expression.

SLC22A2 is abundantly expressed in the kidney and facilitates the transport of endogenous and exogenous cationic compounds. It plays a pivotal role in the transport of pharmacologically important compounds such as metformin, cisplatin, lamivudine and cimetidine. Polymorphisms within SLC22A2 could potentially contribute to the inter-individual variable response to drugs. The SLC22A2 gene is known to show polymorphism variability amongst populations of different ethnicities. The present study was undertaken to characterize the promoter haplotype structure of the SLC22A2 gene in the Xhosa population of South Africa. In addition to this, we also investigate the effects of the observed promoter haplotypes on gene expression levels in vitro. We identified six known single nucleotide polymorphisms in the promoter region, namely rs60249401 (G424A), rs113150889 (G289A), rs55920607 (C246T), rs59695691 (A195G), rs572296424 (G156A), rs150063153 (A95C/G) and one novel SNP at location 6:160258967 (A209T). While these polymorphisms appeared in other African and non-African populations, their minor allele frequencies differed considerably from the non-African populations and could be considered to be African specific. A total of nine promoter haplotypes were characterized and the functional significance of each haplotype on promoter activity was determined using a luciferase reporter assay system. Amongst the nine observed haplotypes, three haplotypes (i.e. haplotypes 7, 8 and 9) displayed a significant decrease in expression level when compared to the wild-type with p -values of: 0.0317, <0.0001 and 0.0013 respectively. The data presented here shows African specific promoter haplotypes to cause a decrease in SLC22A2 gene expression levels, which in turn may have an impact on the pharmacokinetic profiles of cationic drugs.