Tribal ethnicity and CYP2B6 genetics in Ugandan and Zimbabwean populations in the UK: implications for efavirenz dosing in HIV infection

Jamshidi, Yalda; Moreton, Michelle; McKeown, Dermot; Andrews, Susan; Nithiyananthan, T.; Tinworth, Lorna; Holt, David W.; Sadiq, S Tariq

doi:10.1093/jac/dkq369

Cited by 33 publications

(30 citation statements)

References 27 publications

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“…Although cytochrome P450 enzymes play a limited role in metabolizing NRTIs, they do contribute to variability in response to NNRTIs and PIs. The best described enzyme in this context is CYP2B6, which plays a pivotal role in phase I metabolism of efavirenz and to a lesser extent nevirapine [12][13][14][15][16][17]. Decreased metabolism of these NNRTIs results in increased plasma levels and related side effects, including neurotoxicity in the case of efavirenz, and hepatotoxicity when nevirapine is used.…”

Section: Cyp2b6 Cyp2a6 and The Management Of Hiv/aidsmentioning

confidence: 99%

Priority pharmacogenetics for the African continent: focus on CYP450

Alessandrini

Pepper

2014

Pharmacogenomics

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SummaryCountries in Africa have a high burden of communicable disease, and are experiencing an increase in non-communicable diseases due to the effects of globalization, industrialization and urbanization.The costs incurred through adverse drug reactions and non-responsiveness to therapy further aggravate the situation, and the application of pharmacogenetic principles is likely to provide some relief. Having undertaken an extensive evaluation of CYP450 reports in Africa, our objective was to map out areas of need based on regional disease burdens. The data confirms a paucity of CYP450 reports and illustrates large regions for which no population information exists. There is a dire need to address the health problems of Africa, and wide-scale pharmacogenetic profiling of these populations will add significantly to improving patient care on the continent. Priority pharmacogenetics for the African continent gives precedence to the profiling of clinically relevant pharmacogenetic biomarkers, and defines the immediate need in the context of disease burden.

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Section: Cyp2b6 Cyp2a6 and The Management Of Hiv/aidsmentioning

confidence: 99%

Priority pharmacogenetics for the African continent: focus on CYP450

Alessandrini

Pepper

2014

Pharmacogenomics

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“…The CYP2B6 516T/T genotype is especially important in metabolism of anti-cancer and anti-HIV drugs and has been associated with diminished enzyme expression levels resulting in lower efavirenz and nevirapine clearance (50-60%), increased steady-state plasma concentrations and a high frequency of central nervous system (CNS) adverse effects [46,[52][53][54][55][56][57][58]. Interethnic variability in response to the anti-TB drug rifampicin has been explained by variability in CYP2B6 and N-acetyltransferase type 2 (NAT2) expressions [19,59].…”

Section: Implications For Global Pharmacogeneticsmentioning

confidence: 99%

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

Swart¹

2012

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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.

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“…A high allele frequency of 49% for the *6 allele was seen in HIV patients in Zimbabwe (Nyakutira et al, 2008). The CYP2B6*6 allele frequency also differed significantly between a Zimbabwean and a Ugandan population, being 48 and 17% (p50.004), respectively (Jamshidi et al, 2010).…”

Section: Cyp2b6*6 (516g4t and 785a4g)mentioning

confidence: 92%

“…In a study by Radloff et al (2013), eight novel functionally uncharacterized nonsynonymous variants were found in the CYP2B6 gene in a Rwandese population, and it was demonstrated that four of these variants resulted in complete or almost complete loss of function. Three novel SNPs in the CYP2B6 gene were found in a Zimbabwean population (341T4C, 444G4T and 1158A4G), and two novel SNPs in a Ugandan population (856C4T and 1459C4A; Jamshidi et al, 2010). These findings demonstrate the potentially large number of African specific alleles that might exist.…”

Section: Pharmacogenetics In Africamentioning

confidence: 96%

“…The CYP2B6*6 allele was found to be a significant predictor of both plasma and intracellular efavirenz concentrations in both Tanzanian and Ethiopian populations (Ngaimisi et al, 2013). An increase in efavirenz concentration is associated with an increase in the number of loss of function alleles, namely, CYP2B6 *6, *18, *20 and *27, in both Zimbabwean and Ugandan populations, with the number of either the 516G4T or 983T4C alleles having the greatest impact on increasing efavirenz concentrations (Jamshidi et al, 2010). Mukonzo et al (2009) reported a 21% lower oral clearance of efavirenz in another Ugandan population for individuals homozygous for the *6 allele.…”

Section: Cyp2b6*6 (516g4t and 785a4g)mentioning

confidence: 99%

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

Čolić

Alessandrini

Pepper

2014

Drug Metabolism Reviews

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The CYP450 and UGT enzymes are involved in phase I and phase II metabolism of the majority of clinically prescribed drugs, including the non-nucleoside reverse transcriptase inhibitors, efavirenz and nevirapine, used in the treatment of HIV/AIDS. Variations in the activity of these enzymes due to gene polymorphisms can affect an individual's drug response or may lead to adverse drug reactions. There is an inter-ethnic distribution in the frequency of these polymorphisms, with African populations exhibiting higher genetic diversity compared to other populations. African specific alleles with clinical relevance have also emerged. Given the high prevalence of HIV/AIDS in subSaharan Africa, understanding the frequency of pharmacogen-etically relevant alleles in populations of African origin, and their impact on efavirenz and nevirapine metabolism, is becoming increasingly critical. This review aims to investigate ethnic variation of CYP2B6, CYP2A6 and UGT2B7, and to understand the pharmacogenetic relevance when comparing frequencies in African populations to other populations worldwide.

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Tribal ethnicity and CYP2B6 genetics in Ugandan and Zimbabwean populations in the UK: implications for efavirenz dosing in HIV infection

Cited by 33 publications

References 27 publications

Priority pharmacogenetics for the African continent: focus on CYP450

Priority pharmacogenetics for the African continent: focus on CYP450

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

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

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