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

Authors :
Houcemeddine Othman
Sandra Baldwin
Clement Adebamowo
Britt I. Drögemöller
Pamela Thomas
Charles D. Cox
Annette S. Gross
Jorge da Rocha
Samah Ahmed
Gustave Simo
Caroline T. Tiemessen
Sumir Panji
Martin Simuunza
Laura Cottino
Mamana Mbiyavanga
Gerrit Botha
Francisco-Javier Gamo
Michèle Ramsay
Mathias Chiano
Mogomotsi Matshaba
David Twesigomwe
Scott Hazelhurst
Philip Machanick
Faisal M. Fadlelmola
Galen E B Wright
Publication Year :
2020
Publisher :
Cold Spring Harbor Laboratory, 2020.

Abstract

Investigating variation in genes involved in theabsorption, distribution, metabolism, andexcretion(ADME) of drugs are key to characterising pharmacogenomic (PGx) relationships. ADME gene variation is relatively well characterised in European and Asian populations, but African populations are under-studied – which has implications for safe and effective drug use in Africa.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 characterisation of variants in African populations includingin vitroandin silicostudies, and to consider the unique African ADME landscape when developing precision medicine guidelines and tools for African populations.Author summaryThe ADME genes are a group of genes that play a key role in absorption, distribution, metabolism and excretion of drugs. Variations in these genes can have a significant impact on drug safety and efficacy. Africa has a high level of genetic variation and is under-studied in drug development, which makes study of variations in these genes in African populations very important. Using a new data set of 458 high-coverage genomes from across Africa, we characterise the extent and impact of variation in the ADME genes, looking at both single nucleotide and copy number variations. We identified 343,368 variants, including 40,692 novel variants, and 930 coding variants which are predicted to have high impact on function. Our discovery curves indicate that there will be considerable value in sequencing more African genomes. Moreover, relatively few of these novel variants are captured on common genotyping arrays. We show that there is considerable diversity within Africa in some important genes, and this will have significant consequences for the emerging field of precision medicine in Africa.

Details

Database :
OpenAIRE
Accession number :
edsair.doi...........82b013e9e9ad7659baf51229d717779f
Full Text :
https://doi.org/10.1101/2020.06.14.108217