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

被引:25
作者
Frasco, Melissa A. [1 ]
Mack, Wendy J. [1 ]
Van Den Berg, David [1 ]
Aouizerat, Bradley E. [2 ,3 ]
Anastos, Kathryn [4 ,5 ]
Cohen, Mardge [6 ,7 ]
De Hovitz, Jack [8 ]
Golub, Elizabeth T. [9 ]
Greenblatt, Ruth M. [10 ]
Liu, Chenglong [11 ]
Conti, David V. [1 ]
Pearce, Celeste L. [1 ]
机构
[1] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA
[2] Univ Calif San Francisco, Sch Nursing, San Francisco, CA 94143 USA
[3] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA
[4] Montefiore Med Ctr, Dept Med, Bronx, NY 10467 USA
[5] Albert Einstein Coll Med, Bronx, NY 10467 USA
[6] Stroger Hosp, Dept Med, Chicago, IL USA
[7] Rush Univ, Chicago, IL 60612 USA
[8] SUNY Hlth Sci Ctr, Dept Prevent Med & Community Hlth, Brooklyn, NY 11203 USA
[9] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA
[10] Univ Calif San Francisco, Dept Clin Pharm Med Epidemiol & Biostat, San Francisco, CA 94143 USA
[11] Georgetown Univ, Dept Med, Sch Med, Washington, DC USA
关键词
confounding; CYP2B6; nonnucleoside reverse transcriptase inhibitors; population substructure; women; POPULATION STRATIFICATION; ADMIXTURE PROPORTIONS; PLASMA-CONCENTRATIONS; HIV; PHARMACOKINETICS; AFRICAN; ALLELE; PHARMACOGENETICS; INFERENCE; VARIANTS;
D O I
10.1097/QAD.0b013e3283593602
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 anti-retroviral 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 (Cl) 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% Cl 0.79-12.28) and 13.44 (95% Cl 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. (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins
引用
收藏
页码:2097 / 2106
页数:10
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