CYP1A2, CYP2A6, CYP2B6, CYP3A4 and CYP3A5 Polymorphisms in Two Bantu-Speaking Populations from Cameroon and South Africa: Implications for Global Pharmacogenetics

Abstract

The health burden resulting from parasitic and infectious diseases such as HIV/AIDS, tuberculosis and malaria, requires that available medication and limited healthcare resources be used optimally. However, due to co-morbidities, patients are often exposed to many drugs concurrently. Most of these drugs are metabolised by similar enzymes which are polymorphic, thus, drug-drug interactions are a constant problem. Quantitative and qualitative differences in drug metabolizing enzyme variants in different populations result in differential drug response. This study investigated the baseline frequencies of genetic variants in key drug metabolizing cytochrome P450 enzymes, CYP1A2, CYP2A6, CYP2B6, CYP3A4 and CYP3A5 in two previously understudied Bantu-speaking populations from Cameroon (N=72) and South Africa (N=163) using PCR-RFLP. Genotype frequencies for CYP1A2 C-163A and CYP3A4 A-392G single nucleotide polymorphisms (SNPs) were significantly different between these two populations (P=0.0004 and 0.0079, respectively). Significant differences were also observed when the two Bantu-speaking populations were each compared to other African populations as well as Caucasian and Asian populations. Importantly, correspondence analysis showed that the two Bantu-speaking African populations were separated from each other and from other African populations based on CYP1A2 C-163A and CYP2A6 G1093A SNPs. The data show that drugs that are substrates for these polymorphic enzymes are likely to have different response profiles among the Bantu-speaking populations and populations of either Caucasian or Asian origin, further emphasizing the need to genetically characterise as many African populations in order to realize personalised medicine. These data further emphasize that linguistically related Bantu-speaking populations are not necessarily genetically homogenous. Finally, we note that our observations also inform future pharmacogeneticguided rational therapeutic drug monitoring to prevent or minimize the risk for adverse drug-drug interactions mediated by these genetically polymorphic pathways.

Pharmacokinetics of efavirenz in patients on antituberculosis treatment in high human immunodeficiency virus and tuberculosis burden countries: A systematic review

“…Second, the dose difference of EFV used in the two studies. Third, the frequency of genetic polymorphism, given the genotype frequencies in different ethnic African populations as previously reported [71,75].…”

Effects ofCYP2B6andCYP1A2Genetic Variation on Nevirapine Plasma Concentration and Pharmacodynamics as Measured by CD4 Cell Count in Zimbabwean HIV-Infected Patients

“…The major polymorphism in the CYP1A2 gene is a CYP1A2 g.-163C>A SNP where the CYP1A2. g-163A variant has been associated with increased CYP1A2 inducibility, which potentially leads to increased CYP1A2 enzyme levels and increased clearance of CYP1A2 substrate drugs, including EFV and NVP (Aklillu et al, 2003;Basvi et al, 2007;Corchero et al, 2001;Han et al, 2002;Swart et al, 2012). Up to a 70-fold difference in CYP1A2 activity and a 15-fold difference in mRNA expression levels has been reported among individuals (Ikeya et al, 1989;Schweikl et al, 1993).…”

Pharmacogenetics of CYP2B6, CYP2A6 and UGT2B7 in HIV treatment in African populations: focus on efavirenz and nevirapine

“…When two Bantu-speaking populations from Cameroon and South Africa were compared, they were found to be genetically similar with regard to CYP2A6 and CYP2B6. However, there were some statistically significant differences between the genotype frequencies seen in the two populations with respect to CYP1A2, CYP3A4 and CYP3A5 (Swart et al, 2012). The difference in genotype frequencies demonstrates that African populations show intra-ethnic genetic diversity that needs to be characterized appropriately, and that even linguistically related Bantu-speaking populations may not be genetically homogenous.…”

“…The CYP2B6*6 haplotype is characterized by the presence of two nonsynonymous variants 516G4T and 785A4G (Thorn et al, 2010). Strong linkage disequilibrium between 516G4T and 785A4G can be seen in many populations, including Africans, Caucasians, Asians and Hispanics (Li et al, 2012;Maimbo et al, 2012;Mehlotra et al, 2007;Swart et al, 2012Swart et al, , 2013. Substantial inter-population differences in the frequency of the 516G4T and 785A4G SNPs have been reported, with higher frequencies seen in African populations.…”