Pharmacogenomic varia.on in drug transporter encoding genes across African popula.ons

Abstract

Variations in genes encoding enzymes involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs significantly influence drug response across populations. While pharmacogenetic studies in African populations have increased, they predominantly focus on drug metabolism genes, leaving drug transporter genes, such as SLCO1B1 (encoding gene for OATP1B1), underexplored. This gap is particularly critical as variations in SLCO1B1 influence the response to drugs such as statins (cholesterol-lowering agents) and methotrexate (used in chemotherapy). This study aimed to characterize pharmacogenetic variation in SLCO1B1 across African populations. High-depth whole genome sequencing data (n=1080) from sub-Saharan African populations were analysed, drawing from datasets generated by the Human Heredity and Health in Africa (H3Africa) Consortium, the 1000 Genomes Project and other collaborations. The StellarPGx pipeline was used for calling known SLCO1B1 star alleles (i.e. haplotypes and structural variants) and identification of potentially novel haplotypes. Variants were annotated using the Ensembl Variant Effect Predictor (VEP), and missense variants were further evaluated using structural bioinformatics (DDGun) and visualised on OATP1B1 using PyMOL to assess their potential functional and structural impacts. The study identified over 17 unique SLCO1B1 star alleles and five potentially novel haplotypes in sub-Saharan African populations. Star alleles such as *1 and *37, associated with normal function phenotypes, exhibited high frequencies in sub-Saharan African populations. Haplotypes containing missense variants were further analysed and nine of these haplotypes (*9, *15, *19, *20, *27, *28, *30, *31, *44), had negative Gibbs free energy scores, suggesting potential protein destabilisation. These findings underscore the importance of assessing African genomic diversity in pharmacogenomics research to refine drug-response predicJons and develop tailored genotyping panels. Characterizing SLCO1B1 geneJc diversity in African populaJons lays a foundaJon for experimental and clinical funcJonal studies to assay the impact on response to staJns and other medicaJons with a view towards supporJng the broader applicaJon of precision medicine within African populaJons.