Patterns of pharmacogenetic diversity in African populations: role of ancient and recent history

The knowledge that genetic variation influencing drug response is clearly structured among human populations has prompted many studies aimed at obtaining pharmacogenetic profiles in specific populations. While large amounts of data are being produced for populations from developed countries, the African continent still remains very poorly studied. To help to fill this gap, this work characterized three previously uncharacterized African populations for a set of pharmacogenetically relevant polymorphisms.

Seven polymorphic variations in four genes that encode enzymes from phase I (CYP2C9, CYP3A4 and CYP3A5) or phase III (ABCB1) of drug metabolism were analyzed in population samples from Cabinda (n = 107), Mozambique (n = 109) and São Tomé e Príncipe (n = 126). All three populations shared strong recent historical links with Portugal.

The majority of the screened variations displayed large contrasts in allele frequencies between European and African populations, and this study identified a substantial higher European influence in São Tomé e Príncipe than in Cabinda or Mozambique. Admixture analysis demonstrated that the European contribution to the population of São Tomé e Príncipe amounted to 13.3 +/- 3.3%. Furthermore, the proportion of African or European pharmacogenetic ancestry varied widely across each São Tomean individual.

This implies that genetic association studies conducted in São Tomé e Príncipe should take into account the confounding factor of admixture to avoid spurious positive or negative results. Our findings also indicate that drug dosage requirements may be different in São Tomé e Príncipe than in other African populations. Thus, the search for pharmacogenetic risk factors should be assessed at an individual level, therefore fulfilling the perspective of personalized medicine. This study further indicates that the common notion of 'African population' might hide a pattern of pharmacogenetic heterogeneity whose real extent still needs to be evaluated by means of a refined sampling of the entire continent.