title: Organic Cation Transporter 2 (OCT2/SLC22A2) Gene Variation in the South African Bantu-Speaking Population and Functional Promoter Variants.
abstract: SLC22A2 facilitates the transport of endogenous and exogenous cationic compounds. Many pharmacologically significant compounds are transported by SLC22A2, including the antidiabetic drug metformin, anticancer agent cisplatin, and antiretroviral lamivudine. Genetic polymorphisms in SLC22A2 can modify the pharmacokinetic profiles of such important medicines and could therefore prove useful as precision medicine biomarkers. Since the frequency of SLC22A2 polymorphisms varies among different ethnic populations, we evaluated these in South African Bantu speakers, a majority group in the South African population, who exhibit unique genetic diversity, and we subsequently functionally characterized promoter polymorphisms. We identified 11 polymorphisms within the promoter and 9 single-nucleotide polymorphisms (SNPs) within the coding region of SLC22A2. While some polymorphisms appeared with minor allele frequencies similar to other African and non-African populations, some differed considerably; this was especially notable for three missense polymorphisms. In addition, we functionally characterized two promoter polymorphisms; rs138765638, a three base-pair deletion that bioinformatics analysis suggested could alter c-Ets-1/2, Elk1, and/or STAT4 binding, and rs59695691, an SNP that could abolish TFII-I binding. Significantly higher luciferase reporter gene expression was found for rs138765638 (increase of 37%; p = 0.001) and significantly lower expression for rs59695691 (decrease of 25%; p = 0.038), in comparison to the wild-type control. These observations highlight the importance of identifying and functionally characterizing genetic variation in genes of pharmacological significance. Finally, our data for SLC22A2 attest to the importance of considering genetic variation in different populations for drug safety, response, and global pharmacogenomics, through, for example, projects such as the Human Heredity and Health in Africa initiative.
authors.affiliation: 1 The School of Molecular and Cell Biology, University of the Witwatersrand , Johannesburg, South Africa .
authors.forename: Nina C
authors.initials: NC
authors.lastname: Wilson
authors.affiliation: 2 Sydney Brenner Institute for Molecular Bioscience (SBIMB), University of the Witwatersrand , Johannesburg, South Africa .
authors.forename: Ananyo
authors.initials: A
authors.lastname: Choudhury
authors.affiliation: 3 Division of Human Genetics, National Health Laboratory Service , Johannesburg, South Africa .
authors.forename: Nadia
authors.initials: N
authors.lastname: Carstens
authors.affiliation: 1 The School of Molecular and Cell Biology, University of the Witwatersrand , Johannesburg, South Africa .
authors.forename: Demetra
authors.initials: D
authors.lastname: Mavri-Damelin
mesh_terms: D044383:Black People / Q000235:genetics; D005787:Gene Frequency / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006801:Humans; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D000075102:Organic Cation Transporter 2; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D057285:Precision Medicine; D011401:Promoter Regions, Genetic / Q000235:genetics*
chemical_list: D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human
keywords: South Africa; genetic variation; organic cation transporters; personalized medicine; pharmacogenetics