Worldwide variation in human drug-metabolism enzyme genes CYP2B6 and UGT2B7: Implications for HIV/AIDS treatment

Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
Pharmacogenomics (Impact Factor: 3.22). 04/2012; 13(5):555-70. DOI: 10.2217/pgs.11.160
Source: PubMed


Hepatic enzymes, CYP2B6 and UGT2B7 play a major role in the metabolism of the widely used antiretroviral drugs efavirenz, nevirapine and zidovudine. In the present study, we provide a view of UGT2B7 haplotype structure, and quantify the genetic diversity and differentiation at both CYP2B6 and UGT2B7 genes on a worldwide scale.
We genotyped one intronic and three promoter SNPs, and together with three nonsynonymous SNPs, inferred UGT2B7 alleles in north American (n = 326), west African (n = 133) and Papua New Guinean (n = 142) populations. We also included genotype data for five CYP2B6 and six UGT2B7 SNPs from an additional 12 worldwide populations (n = 629) analyzed in the 1000 Genomes Project.
We observed significant differences in certain SNP and allele frequencies of CYP2B6 and UGT2B7 among worldwide populations. Diversity values were higher for UGT2B7 than for CYP2B6, although there was more diversity between populations for CYP2B6. For both genes, most of the genetic variation was observed among individuals within populations, with the Papua New Guinean population showing the highest pairwise differentiation values for CYP2B6, and the Asian and European populations showing higher pairwise differentiation values for UGT2B7.
These new genetic distinctions provide additional insights for investigating differences in antiretroviral pharmacokinetics and therapy outcomes among ethnically and geographically diverse populations.

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    • "Patients with the CYP2B6 c.516G/T and c.516T/T genotypes are reported to be at risk of EFV plasma concentrations associated with toxicity (Lee et al., 2014). Several recent studies performed in Africa have reported a CYP2B6 c.516T-allele frequency ranging from 0.20 to 0.49 (Haas et al., 2004; Klein et al., 2005; Mehlotra et al., 2006; Penzak et al., 2007; Gross et al., 2008; Nyakutira et al., 2008; Mukonzo et al., 2009; Parathyras et al., 2009; Ciccacci et al., 2010; Gounden et al., 2010; Jamshidi et al., 2010; Ikediobi et al., 2011; Brown et al., 2012; Li et al., 2012; Maimbo et al., 2012; Swart et al., 2012b; Ngaimisi et al., 2013; Sarfo et al., 2014; Colic et al., 2015). These studies also reported an association of the CYP2B6 c.516T-allele with high EFV plasma concentrations (Mukonzo et al., 2014; Naidoo et al., 2014; Sarfo et al., 2014; Bisaso et al., 2015; Colic et al., 2015; Dhoro et al., 2015; Dickinson et al., 2015; Sinxadi et al., 2015). "
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    ABSTRACT: Introduction: Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor prescribed as part of first-line highly active antiretroviral therapy (HAART) in South Africa. Despite administration of fixed doses of EFV, inter-individual variability in plasma concentrations has been reported. Poor treatment outcomes such as development of adverse drug reactions or treatment failure have been linked to EFV plasma concentrations outside the therapeutic range (1-4 μg/mL) in some studies. The drug metabolizing enzyme (DME), CYP2B6, is primarily responsible for EFV metabolism with minor contributions by CYP1A2, CYP2A6, CYP3A4, CYP3A5, and UGT2B7. DME coding genes are also regulated by microRNAs through targeting the 3'-untranslated region. Expanded analysis of 30 single nucleotide polymorphisms (SNPs), including those in the 3'-UTR, was performed to identify pharmacogenetics determinants of EFV plasma concentrations in addition to CYP2B6 c.516G>T and c.983T>C SNPs. Methods: SNPs in CYP1A2, CYP2B6, UGT2B7, and NR1I2 (PXR) were selected for genotyping among 222 Bantu-speaking South African HIV-infected patients receiving EFV-containing HAART. This study is a continuation of earlier pharmacogenetics studies emphasizing the role of genetic variation in the 3'-UTR of genes which products are either pharmacokinetic or pharmacodynamic targets of EFV. Results: Despite evaluating thirty SNPs, CYP2B6 c.516G>T and c.983T>C SNPs remain the most prominent predictors of EFV plasma concentration. Conclusion: We have shown that CYP2B6 c.516G>T and c.983T>C SNPs are the most important predictors of EFV plasma concentration after taking into account all other SNPs, including genetic variation in the 3'-UTR, and variables affecting EFV metabolism.
    Full-text · Article · Jan 2016 · Frontiers in Genetics
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    • "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., 2012, 2013). Substantial inter-population differences in the frequency of the 516G4T and 785A4G SNPs have been reported, with higher frequencies seen in African populations. "
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    ABSTRACT: Abstract 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 sub-Saharan Africa, understanding the frequency of pharmacogenetically 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.
    Full-text · Article · Nov 2014 · Drug Metabolism Reviews
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    • "The activity of an enzyme and the gene expression may be modified by single nucleotide polymorphisms (SNPs) [17]. The CYP2B6 sequence carries high variance [21,22] and up to today at least 29 variants have been described [23]. A majority of the variation in CYP450 activity relates to SNPs in the CYP450 gene locus [21]. "
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    ABSTRACT: Background Since human CYP2B6 has been identified as the major CYP enzyme involved in the metabolism of 2,2’,4,4’-tetrabromodiphenyl ether (BDE-47) and that human 2B6 is a highly polymorphic CYP, with known functional variants, we evaluated if circulating concentrations of a major brominated flame retardant, BDE-47, were related to genetic variation in the CYP2B6 gene in a population sample. Methods In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (men and women all aged 70), 25 single nucleotide polymorphisms (SNPs) in the CYP2B6 gene were genotyped. Circulating concentrations of BDE-47 were analyzed by high-resolution gas chromatography coupled to high-resolution mass spectrometry (HRGC/ HRMS). Results Several SNPs in the CYP2B6 gene were associated with circulating concentrations of BDE-47 (P = 10-4 to 10-9). The investigated SNPs came primarily from two haplotypes, although the correlation between the haplotypes was rather high. Conditional analyses adjusting for the SNP with the strongest association with the exposure (rs2014141) did not provide evidence for independent signals. Conclusion Circulating concentrations of BDE-47 were related to genetic variation in the CYP2B6 gene in an elderly population.
    Full-text · Article · May 2014 · Environmental Health
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