Worldwide Variation in Human Drug-Metabolism Enzyme Genes CYP2B6 and UGT2B7 : Implications for HIV/AIDS Treatment

Abstract

Aim 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. Materials & methods 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. Results 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. Conclusion These new genetic distinctions provide additional insights for investigating differences in antiretroviral pharmacokinetics and therapy outcomes among ethnically and geographically diverse populations.

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

“…The remaining 10% of genetic variation occurs between different populations or ancestral groups, i.e. inter-population differences (Li et al, 2012). Li et al (2012) also compared the extent of genetic diversity in the CYP2B6 and UGT2B7 enzymes across a variety of ancestral backgrounds and concluded that genetic variation among individuals within the same population is greater for UGT2B7 than for the highly polymorphic CYP2B6 enzyme.…”

“…inter-population differences (Li et al, 2012). Li et al (2012) also compared the extent of genetic diversity in the CYP2B6 and UGT2B7 enzymes across a variety of ancestral backgrounds and concluded that genetic variation among individuals within the same population is greater for UGT2B7 than for the highly polymorphic CYP2B6 enzyme. However, genetic diversity among individuals in different population groups is higher for CYP2B6 than UGT2B7.…”

“…The CYP2B6*18 allele, characterized by the 983T4C SNP which results in decreased protein expression (Wang et al, 2006), is thought to be an African specific allele. Only individuals of African ancestry and not those of Asian or European ancestry have been reported to carry the allele (Li et al, 2012;Mehlotra et al, 2007). 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.…”

“…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.…”

“…Klein et al (2005) also reported a high frequency of the *6 haplotype in Ghanaians (46.9%), and Sarfo et al (2014) reported a frequency of 48% for the 516G4T SNP in another Ghanaian population. In an analysis of the 1000 genomes database, the 516G4T and 785A4G SNPs were found in 35-38% and 22-35% of populations of African ancestry, respectively, including Luhya (Kenya), Yoruba (Nigeria) and those of African ancestry in the southwestern USA (Li et al, 2012). The 516G4T variant was observed at a frequency of 20-32% in a Xhosa population, and at 23-30% in a Cape mixed ancestry population from South Africa (Ikediobi et al, 2011; Figure 4.…”