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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.