遗传结构基础影响 CYP2B6 多态性与依非韦伦和奈韦拉平反应之间的关联。
Underlying genetic structure impacts the association between CYP2B6 polymorphisms and response to efavirenz and nevirapine.
机构信息
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
出版信息
AIDS. 2012 Oct 23;26(16):2097-106. doi: 10.1097/QAD.0b013e3283593602.
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.
目的
CYP2B6 变异预测其底物的药代动力学特征。考虑到潜在的遗传结构对于防止与高度多态性 CYP2B6 基因产生虚假关联至关重要。
设计
在妇女艾滋病研究机构间研究（Women's Interagency HIV Study）中，探讨了 CYP2B6 变异对其底物（非核苷类逆转录酶抑制剂，NNRTIs）反应的影响。
方法
对 91 名从未接受过抗逆转录病毒药物治疗的妇女，在开始使用 NNRTI 后 1 年内，对 5 种假定的功能性多态性与病毒学抑制的关联进行了检验。生成主成分以控制群体亚结构。采用 logistic 回归检验 rs3745274 和 rs28399499 的联合效应，这两个多态性共同指示慢代谢者、中代谢者和快代谢者。
结果
rs3745274 与病毒学抑制显著相关[比值比=3.61，95%置信区间（CI）1.16-11.22，P 趋势=0.03]；其余检验的多态性与反应无显著关联。中代谢者和慢代谢者与快代谢者相比，实现病毒学抑制的可能性分别为 2.90（95%CI 0.79-12.28）和 13.44（95%CI 1.66 至无穷大），校正主成分后（P 趋势=0.005）。未控制遗传祖源会使代谢表型与治疗反应之间的关系产生很大的混杂。
结论
CYP2B6 代谢表型与 NNRTIs 的病毒学反应显著相关；这种关系可能会被简单地根据自我报告的种族进行调整而掩盖。鉴于自我报告的种族中存在相当大的遗传异质性，这些结果说明了在药物遗传学研究中描述潜在遗传结构的重要性。鉴于这一发现具有潜在的临床重要性，进一步随访 CYP2B6 代谢表型是必要的。
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