Complexities of CYP2D6 gene analysis and interpretation
Complexities of CYP2D6 gene analysis and interpretation
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DOI：
10.3109/09540261.2013.825581
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发表时间：
2013-10-01
影响因子：
2.8
通讯作者：
Gaedigk, Andrea
中科院分区：
文献类型：
--
作者：
Gaedigk, Andrea
细胞色素P450 2D 6（CYP 2D 6）在约25%的临床使用的药物包括许多抗抑郁药、抗精神病药和阿片类药物的代谢和生物活化中起重要作用。CYP 2D 6活性是高度可调的，从所谓的弱代谢者中的无活性到活性分布极端另一端的超速代谢。这种变异性的很大一部分可以通过CYP 2D 6基因座的高度多态性来解释，迄今为止已经鉴定了> 100种变异体和亚变异体。等位基因频率在不同种族群体之间差异很大;有些仅在某些人群中观察到。药物遗传学检测通过识别具有CYP 2D 6双体型的患者，使他们面临剂量相关不良事件或治疗失败的风险增加，从而有望实现个体化药物治疗。然而，由于CYP 2D 6基因位点的复杂性，推断患者的CYP 2D 6代谢能力或表型是一项具有挑战性的任务。等位基因变异包括SNP、小的插入和缺失、基因拷贝数变异和与CYP 2D 7（一个高度相关的非功能基因）的重排。这篇综述总结了CYP 2D 6变异和基因型分析的复杂性，这些知识对于将基因型转化为临床有用的信息非常宝贵。
Cytochrome P450 2D6 (CYP2D6) plays an important role in the metabolism and bioactivation of about 25% of clinically used drugs including many antidepressants, antipsychotics and opioids. CYP2D6 activity is highly variably ranging from no activity in so-called poor metabolizers to ultrarapid metabolism at the other end of the extreme of the activity distribution. A large portion of this variability can be explained by the highly polymorphic nature of the CYP2D6 gene locus for which > 100 variants and subvariants identified to date. Allele frequencies vary markedly between ethnic groups; some have exclusively or predominantly only been observed in certain populations. Pharmacogenetic testing holds the promise of individualizing drug therapy by identifying patients with CYP2D6 diplotypes that puts them at an increased risk of experiencing dose-related adverse events or therapeutic failure. Inferring a patient's CYP2D6 metabolic capacity, or phenotype, however, is a challenging task due to the complexity of the CYP2D6 gene locus. Allelic variation includes SNPs, small insertions and deletions, gene copy number variation and rearrangements with CYP2D7, a highly related nonfunctional gene. This review provides a summary of the intricacies of CYP2D6 variation and genotype analysis, knowledge that is invaluable for the translation of genotype into clinically useful information.