Novel variants of major drug-metabolising enzyme genes in diverse African populations and their predicted functional effects

Abstract

Pharmacogenetics enables personalised therapy based on genetic profiling and is increasingly applied in drug discovery. Medicines are developed and used together with pharmacodiagnostic tools to achieve desired drug efficacy and safety margins. Genetic polymorphism of drug-metabolising enzymes such as cytochrome P450s (CYPs) and N-acetyltransferases (NATs) has been widely studied in Caucasian and Asian populations, yet studies on African variants have been less extensive. The aim of the present study was to search for novel variants of CYP2C9 , CYP2C19 , CYP2D6 and NAT2 genes in Africans, with a particular focus on their prevalence in different populations, their relevance to enzyme functionality and their potential for personalised therapy. Blood samples from various ethnic groups were obtained from the AiBST Biobank of African Populations. The nine exons and exon-intron junctions of the CYP genes and exon 2 of NAT2 were analysed by direct DNA sequencing. Computational tools were used for the identification, haplotype analysis and prediction of functional effects of novel single nucleotide polymorphisms (SNPs). Novel SNPs were discovered in all four genes, grouped to existing haplotypes or assigned new allele names, if possible. The functional effects of non-synonymous SNPs were predicted and known African-specific variants were confirmed, but no significant differences were found in the frequencies of SNPs between African ethnicities. The low prevalence of our novel variants and most known functional alleles is consistent with the generally high level of diversity in gene loci of African populations. This indicates that profiles of rare variants reflecting interindividual variability might become the most relevant pharmacodiagnostic tools explaining Africans' diversity in drug response.

Figure 1

N-acetyltransferase 2 haplotypes constructed from sequence and genotype data from the total population studied (n = 127). (a) Linkage disequilibrium plot with the genomic positions indicated at the top. In yellow are the tag single nucleotide polymorphisms (SNPs) which define the major known haplotypes and are able to capture other SNPs within the same haplotype. The amino acid changes at the various positions are shown. (b) Haplotype frequencies. Haplotypes and phenotypes (acetylators) were assigned according to Consensus Arylamine N-Acetyltransferase (NAT) Gene Nomenclature [31].