Characterization of Novel CYP2D6 Alleles across Sub-Saharan African Populations

Abstract

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.

Estimating the In Vivo Function of CYP2D6 Alleles through Population Pharmacokinetic Modeling of Brexpiprazole

“…22 A recent study of Sub-Saharan African populations described several novel single nucleotide polymorphisms (SNPs) occurring in combination with the SNPs defining CYP2D6*2. 23 Many of these novel alleles were predicted in silico to have deleterious impacts on enzyme function. 23 Such alleles would likely have been reported as CYP2D6*2 by most genotyping assays, which may explain the lower enzyme activity of CYP2D6*2 carriers IIV, interindividual variability expressed as the coefficient of variation calculated as:…”

“…23 Many of these novel alleles were predicted in silico to have deleterious impacts on enzyme function. 23 Such alleles would likely have been reported as CYP2D6*2 by most genotyping assays, which may explain the lower enzyme activity of CYP2D6*2 carriers IIV, interindividual variability expressed as the coefficient of variation calculated as:…”

“…A recent study of Sub‐Saharan African populations described several novel single nucleotide polymorphisms (SNPs) occurring in combination with the SNPs defining CYP2D6*2 23 . Many of these novel alleles were predicted in silico to have deleterious impacts on enzyme function 23 .…”

“… 23 Many of these novel alleles were predicted in silico to have deleterious impacts on enzyme function. 23 Such alleles would likely have been reported as CYP2D6*2 by most genotyping assays, which may explain the lower enzyme activity of CYP2D6*2 carriers of African ancestry observed in some studies. In the current study, no notable difference in CYP2D6 activity was observed between CYP2D6*2 carriers who were African Americans compared with other ethnicities carrying identical CYP2D6 genotypes (see Figure S3 ).…”

PharmVar Tutorial on CYP2D6 Structural Variation Testing and Recommendations on Reporting

“…The selected reactions illustrate the concept of pairing primers that bind to CYP2D6 or CYP2D7 sequences to amplify specific SVs and highlight how certain primer combinations can amplify from multiple loci within an allele or amplify from various SVs. See references for primers, primer pairs, amplification lengths, and other details 30–34,63–65 …”