The Impact of the CYP2D6 "Enhancer" Single Nucleotide Polymorphism on CYP2D6 Activity.
The Impact of the CYP2D6 "Enhancer" Single Nucleotide Polymorphism on CYP2D6 Activity.
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DOI：
10.1002/cpt.2469
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发表时间：
2022-03
影响因子：
6.7
通讯作者：
Gaedigk A
中科院分区：
文献类型：
--
作者：
Dinh JC;Boone EC;Staggs VS;Pearce RE;Wang WY;Gaedigk R;Leeder JS;Gaedigk A
rs5758550 与转录增强有关，并被认为是 CYP2D6 活性的有用标记。由于关于这种遥远“增强子”单核苷酸多态性 (SNP) 的效用的数据有限且不一致，我们的目标是使用体内尿代谢物 (DM; n=188) 和药代动力学 (ATX; n=70) 以及体外代谢物形成，进一步评估 rs5758550 对两种探针底物阿托西汀 (ATX) 和右美沙芬 (DM) 的 CYP2D6 活性的影响（ATX 和 DM；n=166）数据。所有受试者和组织都进行了广泛的基因分型，“增强子”SNP 通过计算或实验与已建立的 CYP2D6 单倍型分相，并使用几个不同复杂性的线性模型研究对 CYP2D6 活性的影响，以确定每个模型捕获的 CYP2D6 活性的变异比例。对于所有数据集和模型，“增强子”SNP 对 CYP2D6 活性预测没有影响或影响不大。如果存在增强效应，则 ATX 比 DM 更明显，表明存在潜在的子状态依赖性。此外，具有“增强子”SNP 的 CYP2D6*2 等位基因在体外与较高的代谢物形成率相关，但在体内则不然；未检测到具有“增强子”SNP 的 CYP2D6*1 等位基因的影响。总之，本次研究中检测到的小效应是否确实是由“增强子”SNP 引起的，还是由于其与基因内其他变体的不完全连锁，目前尚无定论。总而言之，似乎没有足够的证据证明“增强子”SNP 被纳入临床 CYP2D6 药物遗传学测试。
rs5758550 has been associated with enhanced transcription and suggested to be a useful marker of CYP2D6 activity. As there are limited and inconsistent data regarding the utility of this distant “enhancer” single nucleotide polymorphism (SNP), our goal was to further assess the impact of rs5758550 on CYP2D6 activity toward two probe substrates, atomoxetine (ATX) and dextromethorphan (DM), using in vivo urinary metabolite (DM; n=188) and pharmacokinetic (ATX; n=70) and in vitro metabolite formation (ATX and DM; n=166) data. All subjects and tissues were extensively genotyped, the “enhancer” SNP phased with established CYP2D6 haplotypes either computationally or experimentally, and the impact on CYP2D6 activity investigated using several linear models of varying complexity to determine the proportion of variability in CYP2D6 activity captured by each model. For all datasets and models, the “enhancer” SNP had no or only a modest impact on CYP2D6 activity prediction. An increased effect, when present, was more pronounced for ATX than DM suggesting potential substate-dependency. In addition, CYP2D6*2 alleles with the “enhancer” SNP were associated with modestly higher metabolite formation rates in vitro, but not in vivo; no effect was detected for CYP2D6*1 alleles with “enhancer” SNP. In summary, it remains inconclusive whether the small effects detected in this investigation are indeed caused by the “enhancer” SNP or are rather due to its incomplete linkage with other variants within the gene. Taken together, there does not appear to be sufficient evidence to warrant the “enhancer” SNP be included in clinical CYP2D6 pharmacogenetic testing.
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影响因子：
6.7
作者：
Goetz MP;Sangkuhl K;Guchelaar HJ;Schwab M;Province M;Whirl-Carrillo M;Symmans WF;McLeod HL;Ratain MJ;Zembutsu H;Gaedigk A;van Schaik RH;Ingle JN;Caudle KE;Klein TE
通讯作者：
Klein TE
影响因子：
6.7
作者：
Ning M;Duarte JD;Rubin LH;Jeong H
通讯作者：
Jeong H
影响因子：
6.7
作者：
Crews KR;Monte AA;Huddart R;Caudle KE;Kharasch ED;Gaedigk A;Dunnenberger HM;Leeder JS;Callaghan JT;Samer CF;Klein TE;Haidar CE;Van Driest SL;Ruano G;Sangkuhl K;Cavallari LH;Müller DJ;Prows CA;Nagy M;Somogyi AA;Skaar TC
通讯作者：
Skaar TC
影响因子：
6.7
作者：
Frederiksen T;Areberg J;Schmidt E;Bjerregaard Stage T;Brøsen K
通讯作者：
Brøsen K
影响因子：
2.9
作者：
Chládek, J;Zimová, G;Tuma, I
通讯作者：
Tuma, I