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

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dc.contributor.authorMatimba, Aliceen_ZA
dc.contributor.authorDel-Favero, Jurgenen_ZA
dc.contributor.authorVan Broeckhoven, Christineen_ZA
dc.contributor.authorMasimirembwa, Collenen_ZA
dc.date.accessioned2015-10-30T09:33:23Z
dc.date.available2015-10-30T09:33:23Z
dc.date.issued2009en_ZA
dc.description.abstractPharmacogenetics 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.en_ZA
dc.identifier.apacitationMatimba, A., Del-Favero, J., Van Broeckhoven, C., & Masimirembwa, C. (2009). Novel variants of major drug-metabolising enzyme genes in diverse African populations and their predicted functional effects. <i>Human Genomics</i>, http://hdl.handle.net/11427/14522en_ZA
dc.identifier.chicagocitationMatimba, Alice, Jurgen Del-Favero, Christine Van Broeckhoven, and Collen Masimirembwa "Novel variants of major drug-metabolising enzyme genes in diverse African populations and their predicted functional effects." <i>Human Genomics</i> (2009) http://hdl.handle.net/11427/14522en_ZA
dc.identifier.citationMatimba, A., Del-Favero, J., Van Broeckhoven, C., & Masimirembwa, C. (2009). Novel variants of major drug-metabolising enzyme genes in diverse African populations and their predicted functional effects. Hum Genomics, 3(2), 169-190.en_ZA
dc.identifier.ris TY - Journal Article AU - Matimba, Alice AU - Del-Favero, Jurgen AU - Van Broeckhoven, Christine AU - Masimirembwa, Collen AB - 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. DA - 2009 DB - OpenUCT DO - 10.1186/1479-7364-3-2-169 DP - University of Cape Town J1 - Human Genomics LK - https://open.uct.ac.za PB - University of Cape Town PY - 2009 T1 - Novel variants of major drug-metabolising enzyme genes in diverse African populations and their predicted functional effects TI - Novel variants of major drug-metabolising enzyme genes in diverse African populations and their predicted functional effects UR - http://hdl.handle.net/11427/14522 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/14522
dc.identifier.urihttp://dx.doi.org/10.1186/1479-7364-3-2-169
dc.identifier.vancouvercitationMatimba A, Del-Favero J, Van Broeckhoven C, Masimirembwa C. Novel variants of major drug-metabolising enzyme genes in diverse African populations and their predicted functional effects. Human Genomics. 2009; http://hdl.handle.net/11427/14522.en_ZA
dc.language.isoengen_ZA
dc.publisherBioMed Central Ltden_ZA
dc.publisher.departmentDivision of Human Geneticsen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis is an Open Access article distributed under the terms of the Creative Commons Attribution Licenseen_ZA
dc.rights.holder2009 Henry Stewart Publicationsen_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/2.0en_ZA
dc.sourceHuman Genomicsen_ZA
dc.source.urihttp://www.humgenomics.com/en_ZA
dc.subject.otherpharmacogeneticsen_ZA
dc.subject.othercytochrome P450en_ZA
dc.subject.otherN-acetyltransferaseen_ZA
dc.subject.othersingle nucleotide polymorphismsen_ZA
dc.subject.otherAfrican populationsen_ZA
dc.titleNovel variants of major drug-metabolising enzyme genes in diverse African populations and their predicted functional effectsen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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