Cytochrome P4502D6 (CYP2D6) gene locus heterogeneity:: Characterization of gene duplication events
Cytochrome P4502D6 (CYP2D6) gene locus heterogeneity:: Characterization of gene duplication events
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DOI：
10.1038/sj.clpt.6100033
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发表时间：
2007-02-01
影响因子：
6.7
通讯作者：
Leeder, J. Steven
中科院分区：
文献类型：
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作者：
Gaedigk, A.;Ndjountche, L.;Leeder, J. Steven
活性 CYP2D6 基因的重复和倍增可导致药物代谢超快并导致治疗失败。多个功能性和非功能性重复等位基因已得到进一步表征。通过长程聚合酶链式反应 (PCR)、PCR 限制性片段长度多态性和序列分析来检测重复。使用包含整个重复基因的 PCR 片段进行详细表征。在白种人、非裔美国人和种族混合人群中，重复发生率分别为 1.3%、5.75% 和 2.0%（总共 n = 887）。其中 28%、47% 和 17% 为非功能性 CYP2D6*4 x N。检测到 12 个独特的重复等位基因：*1 x N、*2 x N、*4 x N、*6 x N、*10 x N、*17 x N、*17 x N[间隔区]、*29 x N、*35 x N、*43 x N、*45 x N 和一种新颖的非功能性串联排列嵌合 2D7/2D6 和 *1 基因。除 *35 x N 外，所有新的重复均在非裔美国人中发现。准确识别基因重复事件对于避免假阳性超快速代谢分配至关重要，从而避免高估预测活性并增加不良不良事件的风险。
Duplications and multiplications of active CYP2D6 genes can cause ultrarapid drug metabolism and lead to therapeutic failure. Multiple functional and non-functional duplication alleles have been further characterized. Duplications were detected by long-range polymerase chain reaction (PCR), PCR-restriction fragment length polymorphism, and sequence analysis. A PCR fragment encompassing the entire duplicated gene was utilized for detailed characterization.Duplications occurred at 1.3, 5.75, and 2.0% in Caucasian, African American, and racially mixed populations, respectively (n = 887 total). Of those 28, 47, and 17% were non-functional CYP2D6*4 x N. Twelve unique duplication alleles were detected: *1 x N, *2 x N, *4 x N, *6 x N, *10 x N, *17 x N, *17 x N[spacer], *29 x N, *35 x N, *43 x N, *45 x N, and a novel non-functional tandem arrangement of a chimeric 2D7/2D6 and *1 gene. All novel duplications except *35 x N were found in African Americans. Accurate identification of gene duplication events is essential to avoid false-positive ultrarapid metabolism assignments and thus, overestimation of predicted activity and increased risk for unwanted adverse events.