The majority of pharmacogenetic studies are performed in

The majority of pharmacogenetic studies are performed in Asian and Caucasian populations; data generated in African-American populations are sometimes extrapolated to represent the population of the African continent. However, the ancestry of African-Americans is predominantly from Niger-Kordofanian (~71%), European (~13%), and other African (~8%) populations (Tishkoff et al., 2009). It is therefore unlikely that the African-American population will be representative of the many different populations present in Africa. Raising awareness of the greater genetic variability in Africa and its relevance to drug Rapalink-1 and efficacy, and the requirement for further pharmacogenetic and clinical studies in African populations, has the potential to result in modifications to drug regimens that could reduce the risk of adverse drug reactions and the overall disease burden. Here, we provide a comprehensive and up-to-date review of the frequencies of known CYP variants in African populations. In addition, we use principal components analysis to compare these with data from Asian and Caucasian populations. Such analyses can identify CYP variants demonstrating a marked difference in distribution in Africa, and African regions or populations that may be at a higher risk of drug toxicity or inefficacy. The findings of our study may help to support the future pharmacogenetic profiling of Africa which may be of relevance to both clinical therapeutics and drug research and development.
Methods
Results The initial literature search returned a total of 368 publications, 58 of which reported CYP frequencies in African populations. An additional 22 publications were obtained from the PubMed search (Fig. 1). CYP frequencies obtained for African populations are summarized in Supplemental Tables 1 and 2. Clinically relevant CYP substrates are detailed in Supplemental Tables 1 and 3. Of the 74 papers cited as the basis of population-specific CYP allele frequencies in Supplemental Table 1 (Table 1), only 12 utilized genotyping methodologies capable of detecting novel sequence variations (Bains et al., 2013; Xiong et al., 2011; Chen et al., 2008; Klein et al., 2005; Park et al., 2008; Lee et al., 2006; Leathart et al., 1998; Gaedigk and Coetsee, 2008; Dickmann et al., 2001; Drögemöller et al., 2010; Wright et al., 2010; Dodgen et al., 2013). Of these, four were in Asian populations (two Chinese [Xiong et al., 2011; Chen et al., 2008]; two Korean [Park et al., 2008; Lee et al., 2006]) and eight involved Africans or African-Americans (Bains et al., 2013; Klein et al., 2005; Gaedigk and Coetsee, 2008; Leathart et al., 1998; Dickmann et al., 2001; Drögemöller et al., 2010; Wright et al., 2010; Dodgen et al., 2013). The analysis in SIMCA used three principal components; PC1 and PC2 described most of the variance in the data set and were therefore further analyzed. PCA demonstrated distinct clustering of African, Asian and Caucasian populations (Fig. 2), with the exception of Xhosa (South Africa; positioned outside of the three clusters). The lack of available CYP frequency data for admixed populations in South Africa prevented further analysis of this result. While Caucasian and Asian populations demonstrated tight clustering, a considerably greater variability in CYP frequencies was observed across Africa as indicated by the widespread distribution of the African populations on the PCA plot (Fig. 2). The following CYP variants showed a marked difference in distribution in African populations compared with other global populations: CYP2B6*6, CYP2C8*2, CYP2D6*3, CYP2D6*17, CYP2D6*29, CYP3A5*6 and CYP3A5*7 (Fig. 2). Our literature review also identified reports of polymorphisms in CYP2A6 (*17) and CYP2B6 (*33–*37) that have not been reported in populations outside of Africa (Supplemental Table 1, Table 2). In addition, African populations with the highest and lowest frequencies for certain CYP alleles are presented in Table 1. Of the 17 CYP variants selected for PCA, the greatest differences in reported frequencies were observed for CYP2B6*6 (highest reported frequency: Uganda, 69%; lowest reported frequency: South Africa mixed ancestry, 9%), CYP2C9*3 (Libya, 35%; Ghana, 0%), CYP2D6*17 (Shona, 34%; Democratic Republic of Congo, 0%) and CYP3A5*3 (Morocco, 92%; Uganda, 4%). Frequencies were very similar among African populations for CYP2D6*9 (0% in all populations investigated) and CYP2C8*4 (Tanzania, 0.6%; Ghana, 0%).