The Extent and Impact of Variation in ADME Genes in Sub-Saharan African Populations

Abstract

Introduction: 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.Results: We identified significant ADME gene variation in African populations using data from 458 high-coverage whole genome sequences, 412 of which are novel, and from previously available African sequences from the 1,000 Genomes Project. ADME variation was not uniform across African populations, particularly within high impact coding variation. Copy number variation was detected in 116 ADME genes, with equal ratios of duplications/deletions. We identified 930 potential high impact coding variants, of which most are discrete to a single African population cluster. Large frequency differences (i.e., >10%) were seen in common high impact variants between clusters. Several novel variants are predicted to have a significant impact on protein structure, but additional functional work is needed to confirm the outcome of these for PGx use. Most variants of known clinical outcome are rare in Africa compared to European populations, potentially reflecting a clinical PGx research bias to European populations.Discussion: The genetic diversity of ADME genes across sub-Saharan African populations is large. The Southern African population cluster is most distinct from that of far West Africa. PGx strategies based on European variants will be of limited use in African populations. Although established variants are important, PGx must take into account the full range of African variation. This work urges further characterization of variants in African populations including in vitro and in silico studies, and to consider the unique African ADME landscape when developing precision medicine guidelines and tools for African populations.

Characterization of ADME Gene Variation in Colombian Population by Exome Sequencing

“…Our study found that cytochrome P450 ( CYP540 ) genes harbor many rare variants in agreement with previous reports ( Fujikura et al, 2015 ; Wright et al, 2018 ; Tasa et al, 2019 ; da Rocha et al, 2021 ). Considering that approximately 79% of widely used drugs are metabolized by enzymes of the CYP450 family, the impact of rare variants potentially related to the generation of ADRs in the sampled population is significant ( Phillips et al, 2001 ; Zanger and Schwab, 2013 ; Fujikura et al, 2015 ; Tornio and Backman, 2018 ).…”

African Genomic Medicine Portal: A Web Portal for Biomedical Applications

“…Recent advances in genomics have illustrated the rich genetic diversity of African populations [4,5] and its associated health implications, such as varying lipid profiles [6], predisposition to kidney disease [7] and more [8]. Similar diversity has been observed in pharmacogenomics studies, where, for example, population-specific alleles and frequencies have been found in the genes encoding the cytochrome P450 (CYP) enzymes in Africans, together with structural variants that impact enzymes functionality [9][10][11].…”

“…SNVs and star alleles, stored in the 'Variant' table, provide information about the variants, and these are associated with phenotypes, which could be related to either the response to a drug or a disease. The star allele variants from PharmGKB were retrieved to account for the particularity of annotating the absorption distribution metabolism excretion (ADME) genes [10]. Note, that a star allele is defined by a set of core variants that define the phenotype associated with the drug response in linkage disequilibrium with other variants, of which presence or absence is not necessarily related to the drug-response phenotype [17][18][19].…”

SWAAT Bioinformatics Workflow for Protein Structure-Based Annotation of ADME Gene Variants

“…Its occurrence among genetically diverse groups (reflected in self-identify) in South Africa has been shown to vary significantly even among geographically neighboring populations [3]. Moreover, clinically actionable variants of ADME genes deviate significantly between Sub-Saharan Africa and other worldwide populations [7].…”

“…However, these variants cannot solely explain the wide range of observed drug-response phenotypes [8]. In particular, rare variants were shown to have an important share of the genetic makeup and were identified for their putative functional implication in ADME genes [5,7,9,10]. The important status of rare variants has been also highlighted recently as critical to consider in deriving personalized medicine strategies [11].…”