The extent and impact of variation in ADME genes in sub-Saharan African populations

Investigating variation in genes involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs are key to characterizing pharmacogenomic (PGx) relationships. ADME gene variation is relatively well characterized in European and Asian populations, but data from African populations are under-studied—which has implications for drug safety and effective use in Africa

Characterization of POR haplotype distribution in African populations and comparison with other global populations: Supplementary tables

Background & aim: POR is an enzyme that mediates electron transfer to enable the drug-metabolizing activity of CYP450 proteins. However, POR has been understudied in pharmacogenomics despite this vital role. The authors aimed to characterize the genetic variation in POR across African populations and to compare the star allele (haplotype) distribution with that in other global populations. Materials & methods: POR star alleles were called from whole-genome sequencing data using the StellarPGx pipeline. Results: In addition to the common POR*1 and *28 haplotypes (defined by rs1057868), five novel rare haplotypes were computationally inferred. No significant frequency differences were observed among the majority of African populations. However, POR*28 was observed at a higher frequency in individuals of non-African ancestry. Conclusion: This study highlights the distribution of POR alleles in Africa and across global populations with a view toward informing future precision medicine implementation.</p

The variation landscape of CYP2D6 in a multi-ethnic Asian population

Abstract Cytochrome P450 2D6 (CYP2D6) plays a crucial role in metabolizing approximately 20% of medications prescribed clinically. This enzyme is encoded by the CYP2D6 gene, known for its extensive polymorphism with over 170 catalogued haplotypes or star alleles, which can have a profound impact on drug efficacy and safety. Despite its importance, a gap exists in the global genomic databases, which are predominantly representative of European ancestries, thereby limiting comprehensive knowledge of CYP2D6 variation in ethnically diverse populations. In an effort to bridge this knowledge gap, we focused on elucidating the CYP2D6 variation landscape within a multi-ethnic Asian cohort, encompassing individuals of Chinese, Malay, and Indian descent. Our study comprised data analysis of 1850 whole genomes from the SG10K_Health dataset using an in-house consensus algorithm, which integrates the capabilities of Cyrius, Aldy, and StellarPGx. This analysis unveiled distinct population-specific star-allele distribution trends, highlighting the unique genetic makeup of the Singaporean population. Significantly, 46% of our cohort harbored actionable CYP2D6 variants—those with direct implications for drug dosing and treatment strategies. Furthermore, we identified 14 potential novel CYP2D6 star-alleles, of which 7 were observed in multiple individuals, suggesting their broader relevance. Overall, our study contributes novel data on CYP2D6 genetic variations specific to the Southeast Asian context. The findings are instrumental for the advancement of pharmacogenomics and personalized medicine, not only in Southeast Asia but also in other regions with comparable genetic diversity

Characterization of Novel CYP2D6 Alleles across Sub-Saharan African Populations

The CYP2D6 gene has been widely studied to characterize variants and/or star alleles, which account for a significant portion of variability in drug responses observed within and between populations. However, African populations remain under-represented in these studies. The increasing availability of high coverage genomes from African populations has provided the opportunity to fill this knowledge gap. In this study, we characterized computationally predicted novel CYP2D6 star alleles in 30 African subjects for whom DNA samples were available from the Coriell Institute. CYP2D6 genotyping and resequencing was performed using a variety of commercially available and laboratory-developed tests in a collaborative effort involving three laboratories. Fourteen novel CYP2D6 alleles and multiple novel suballeles were identified. This work adds to the growing catalogue of validated African ancestry CYP2D6 allelic variation in pharmacogenomic databases, thus laying the foundation for future functional studies and improving the accuracy of CYP2D6 genotyping, phenotype prediction, and the refinement of clinical pharmacogenomic implementation guidelines in African and global settings