Underlying genetic structure impacts the association between CYP2B6 polymorphisms and response to efavirenz and nevirapine

Melissa A. Frasco, Wendy J. MacK, David Van Den Berg, Bradley E. Aouizerat, Kathryn Anastos, Mardge Cohen, Jack De Hovitz, Elizabeth T. Golub, Ruth M. Greenblatt, Chenglong Liu, David V. Conti, Celeste L. Pearce

Research output: Contribution to journalArticle

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. DESIGN: 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. CONCLUSION: 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.

Original languageEnglish (US)
Pages (from-to)2097-2106
Number of pages10
JournalAIDS
Volume26
Issue number16
DOIs
StatePublished - Oct 23 2012

Fingerprint

efavirenz
Nevirapine
Genetic Structures
Reverse Transcriptase Inhibitors
Confidence Intervals
Phenotype
Anti-Retroviral Agents
Genetic Heterogeneity
Pharmacokinetics
Logistic Models
Odds Ratio
Cytochrome P-450 CYP2B6
HIV

Keywords

  • confounding
  • CYP2B6
  • nonnucleoside reverse transcriptase inhibitors
  • population substructure
  • women

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Underlying genetic structure impacts the association between CYP2B6 polymorphisms and response to efavirenz and nevirapine. / Frasco, Melissa A.; MacK, Wendy J.; Van Den Berg, David; Aouizerat, Bradley E.; Anastos, Kathryn; Cohen, Mardge; De Hovitz, Jack; Golub, Elizabeth T.; Greenblatt, Ruth M.; Liu, Chenglong; Conti, David V.; Pearce, Celeste L.

In: AIDS, Vol. 26, No. 16, 23.10.2012, p. 2097-2106.

Research output: Contribution to journalArticle

Frasco, MA, MacK, WJ, Van Den Berg, D, Aouizerat, BE, Anastos, K, Cohen, M, De Hovitz, J, Golub, ET, Greenblatt, RM, Liu, C, Conti, DV & Pearce, CL 2012, 'Underlying genetic structure impacts the association between CYP2B6 polymorphisms and response to efavirenz and nevirapine', AIDS, vol. 26, no. 16, pp. 2097-2106. https://doi.org/10.1097/QAD.0b013e3283593602
Frasco, Melissa A. ; MacK, Wendy J. ; Van Den Berg, David ; Aouizerat, Bradley E. ; Anastos, Kathryn ; Cohen, Mardge ; De Hovitz, Jack ; Golub, Elizabeth T. ; Greenblatt, Ruth M. ; Liu, Chenglong ; Conti, David V. ; Pearce, Celeste L. / Underlying genetic structure impacts the association between CYP2B6 polymorphisms and response to efavirenz and nevirapine. In: AIDS. 2012 ; Vol. 26, No. 16. pp. 2097-2106.
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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. DESIGN: 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. CONCLUSION: 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.",
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AU - Frasco, Melissa A.

AU - MacK, Wendy J.

AU - Van Den Berg, David

AU - Aouizerat, Bradley E.

AU - Anastos, Kathryn

AU - Cohen, Mardge

AU - De Hovitz, Jack

AU - Golub, Elizabeth T.

AU - Greenblatt, Ruth M.

AU - Liu, Chenglong

AU - Conti, David V.

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N2 - 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. DESIGN: 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. CONCLUSION: 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.

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