title: Underlying genetic structure impacts the association between CYP2B6 polymorphisms and response to efavirenz and nevirapine.
abstract: OBJECTIVE
  CYP2B6 variation predicts pharmacokinetic characteristics of its substrates. Consideration for underlying genetic structure is critical to protect against spurious associations with the highly polymorphic CYP2B6 gene.
  
  
  METHODS
  The effect of CYP2B6 variation on response to its substrates, nonnucleoside reverse transcriptase inhibitors (NNRTIs), was explored in the Women's Interagency HIV Study.
  
  
  METHODS
  Five putative functional polymorphisms were tested for associations with virologic suppression within 1 year after NNRTI initiation in women naive to antiretroviral agents (n = 91). Principal components were generated to control for population substructure. Logistic regression was used to test the joint effect of rs3745274 and rs28399499, which together indicate slow, intermediate, and extensive metabolizers.
  
  
  RESULTS
  Rs3745274 was significantly associated with virologic suppression [odds ratio = 3.61, 95% confidence interval (CI) 1.16-11.22, P trend = 0.03]; the remaining polymorphisms tested were not significantly associated with response. Women classified as intermediate and slow metabolizers were 2.90 (95% CI 0.79-12.28) and 13.44 (95% CI 1.66 to infinity) times as likely to achieve virologic suppression compared to extensive metabolizers after adjustment for principal components (P trend = 0.005). Failure to control for genetic ancestry resulted in substantial confounding of the relationship between the metabolizer phenotype and treatment response.
  
  
  CONCLUSIONS
  The CYP2B6 metabolizer phenotype was significantly associated with virologic response to NNRTIs; this relationship would have been masked by simple adjustment for self-reported ethnicity. Given the appreciable genetic heterogeneity that exists within self-reported ethnicity, these results exemplify the importance of characterizing underlying genetic structure in pharmacogenetic studies. Further follow-up of the CYP2B6 metabolizer phenotype is warranted, given the potential clinical importance of this finding.
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Frasco
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Mack
authors.forename: David
authors.initials: D
authors.lastname: Van Den Berg
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Aouizerat
authors.forename: Kathryn
authors.initials: K
authors.lastname: Anastos
authors.forename: Mardge
authors.initials: M
authors.lastname: Cohen
authors.forename: Jack
authors.initials: J
authors.lastname: De Hovitz
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Golub
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Greenblatt
authors.forename: Chenglong
authors.initials: C
authors.lastname: Liu
authors.forename: David V
authors.initials: DV
authors.lastname: Conti
authors.forename: Celeste L
authors.initials: CL
authors.lastname: Pearce
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000453:epidemiology / Q000276:immunology; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000187:drug effects*; D048588:Benzoxazines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D019829:Nevirapine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D010089:Oxidoreductases, N-Demethylating / Q000187:drug effects*; D020641:Polymorphism, Single Nucleotide; D014481:United States / Q000453:epidemiology; D019562:Viral Load
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D019829:Nevirapine; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; C098320:efavirenz