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

Pharmacogenomics. 2012 Apr;13(5):555-70. doi: 10.2217/pgs.11.160.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • African Continental Ancestry Group / genetics
  • Anti-HIV Agents / pharmacokinetics*
  • Anti-HIV Agents / therapeutic use
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Asian Continental Ancestry Group / genetics
  • Cytochrome P-450 CYP2B6
  • European Continental Ancestry Group / genetics
  • Gene Frequency
  • Genotype
  • Glucuronosyltransferase / genetics*
  • HIV Infections / drug therapy*
  • HIV Infections / enzymology
  • HIV Infections / genetics
  • HapMap Project
  • Human Genome Project
  • Humans
  • Oxidoreductases, N-Demethylating / genetics*
  • Papua New Guinea
  • Polymorphism, Single Nucleotide*

Substances

  • Anti-HIV Agents
  • Aryl Hydrocarbon Hydroxylases
  • CYP2B6 protein, human
  • Cytochrome P-450 CYP2B6
  • Oxidoreductases, N-Demethylating
  • UGT2B7 protein, human
  • Glucuronosyltransferase