CYP2D6基因分型影响因素研究进展

doi:10.3969/j.issn.1673-8640.2024.03.015

摘要/Abstract

摘要：

细胞色素P450家族2亚科D成员6（CYP2D6）是细胞色素P450酶家族中的重要药物代谢酶，是抗抑郁药物、抗精神病药物和阿片类镇痛药物等主要的代谢酶。CYP2D6基因位点的复杂性和诸多等位基因突变体造成了CYP2D6表型的多态性，目前已报道170余种等位基因突变体。CYP2D6酶活性变化很大，从无活性到超快代谢均存在，根据酶活性可将不同表型携带者分为超快代谢者、正常代谢者、中间代谢者和弱代谢者。随着个体化医疗的发展，CYP2D6基因分型试验可以辅助药物遗传学和基因分型技术的研究和临床应用。然而，由于CYP2D6基因存在复杂的突变，包括单核苷酸突变、插入、缺失、基因拷贝数变异和基因重组。CYP2D6基因不仅存在个体化差异，且在不同种族之间等位基因的频率也明显不同。另外，人体内同时存在与CYP2D6同源性很高的非功能性基因CYP2D7，通过基因检测分析CYP2D6表型是一项非常具有挑战性的工作。文章总结了CYP2D6基因的多态性和基因分型的复杂性，并分析了部分不同的基因型突变对CYP2D6基因分型的影响，以帮助临床通过基因分型方法对CYP2D6酶活性进行预测。

关键词: 细胞色素P450家族2亚科D成员6, 基因分型, 突变, 等位基因, 基因多态性

Abstract:

Cytochrome P450 family 2 subfamily D member 6（CYP2D6）is one of most important drug metabolism enzymes in the cytochrome P450 family. It mainly metabolizes many drugs，including antidepressants，antipsychotics and opioids. The complexity of CYP2D6 gene locus and allelic variation can be translated into the polymorphism of CYP2D6. To date，over 170 allelic variations have been published. CYP2D6 activity is highly variably ranging from no activity to ultrarapid metabolism. The phenotypes are categorized into ultrarapid metabolizer，normal metabolizer，intermediate metabolizer and poor metabolizer. With the development of individualized medicine，the CYP2D6 genotyping can utilize the pharmacogenetics and genotyping as part of the clinical decision-making process. The complexity of CYP2D6 allelic variations includes single nucleotide polymorphism，insertion，deletion，gene copy number variation and gene rearrangement. The CYP2D6 gene not only had individualized differences，but also the frequency of alleles between different races was different. Furthermore，CYP2D6 had a non-functional gene CYP2D7 with high homology，so its phenotype prediction by CYP2D6 genotyping was a challenging task. This review summarizes the polymorphism of CYP2D6 gene and the complexity of CYP2D6 genotyping，and also summarizes the impact of different allelic variations on CYP2D6 genotyping. It is valuable for clinical laboratories to perform CYP2D6 genotyping for phenotype prediction in the future.

Key words: Cytochrome P450 family 2 subfamily D member 6, Genotyping, Variation, Allele, Gene polymorphism

中图分类号:

R446.7

慎津进, 薛寒, 李进福, 高利飞, 郑业焕. CYP2D6基因分型影响因素研究进展[J]. 检验医学, 2024, 39(3): 291-297.

SHEN Jinjin, XUE Han, LI Jinfu, GAO Lifei, ZHENG Yehuan. Research progress on the factors of CYP2D6 genotyping[J]. Laboratory Medicine, 2024, 39(3): 291-297.

图/表 1

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等位基因	活性评分/分	东亚人群频率/%	等位基因功能	基因突变
*1	1.0	25.78	正常
*1×2	2.0	0.34	提高	*1双拷贝基因
*2	1.0	11.92	正常	2851C>T，4181G>C
*2×2	2.0	0.46	提高	*2双拷贝基因
*2×≥3	≥3.0	0.10	提高	*2至少有三拷贝基因
*4	0.0	0.53	无	1847G>A
*5	0.0	4.82	无	CYP2D6整基因缺失
*9	0.25	0.17	减弱	2616delAAG
*10	0.25	42.84	减弱	100C>T，4181G>C
*10×2	0.5	0.59	减弱	*10双拷贝基因
*13	0.0	0.13	无	CYP2D7-CYP2D6 hybrid gene
*14	0.5	0.47	减弱	1759G>A，2851C>T，4181G>C
*18	0.0	0.13	无	4135-4136insTGCCCACTG
*21	0.0	0.35	无	2580-2581insC，2851C>T，4181G>C
*34	1.0	0.89	正常	2851C>T
*36	0.0	1.14	无	100C>T， 4129C>G，4132A>G，4156C>T+4157A>C，4159G>C，4165T>G，4168G>A+4169C>G，4181G>C
*36×2	0.0	0.41	无	*36双拷贝基因
*39	1.0	0.56	正常	4181G>C
*41	0.25	2.32	减弱	2851C>T，2989G>A，4181G>C
*49	0.5	0.99	减弱	100C>T，1612T>A，4181G>C
*52	0.25	0.16	减弱	100C>T，3878G>A，4181G>C
*60	0.0	0.14	无	1888-1889insTA
*65		2.95	功能不清	100C>T，2851C>T，4181G>C
*69	0.0	1.00	无	100C>T，2851C>T，2989G>A，4181G>C

等位基因	活性评分/分	东亚人群频率/%	等位基因功能	基因突变
*1	1.0	25.78	正常
*1×2	2.0	0.34	提高	*1双拷贝基因
*2	1.0	11.92	正常	2851C>T，4181G>C
*2×2	2.0	0.46	提高	*2双拷贝基因
*2×≥3	≥3.0	0.10	提高	*2至少有三拷贝基因
*4	0.0	0.53	无	1847G>A
*5	0.0	4.82	无	CYP2D6整基因缺失
*9	0.25	0.17	减弱	2616delAAG
*10	0.25	42.84	减弱	100C>T，4181G>C
*10×2	0.5	0.59	减弱	*10双拷贝基因
*13	0.0	0.13	无	CYP2D7-CYP2D6 hybrid gene
*14	0.5	0.47	减弱	1759G>A，2851C>T，4181G>C
*18	0.0	0.13	无	4135-4136insTGCCCACTG
*21	0.0	0.35	无	2580-2581insC，2851C>T，4181G>C
*34	1.0	0.89	正常	2851C>T
*36	0.0	1.14	无	100C>T， 4129C>G，4132A>G，4156C>T+4157A>C，4159G>C，4165T>G，4168G>A+4169C>G，4181G>C
*36×2	0.0	0.41	无	*36双拷贝基因
*39	1.0	0.56	正常	4181G>C
*41	0.25	2.32	减弱	2851C>T，2989G>A，4181G>C
*49	0.5	0.99	减弱	100C>T，1612T>A，4181G>C
*52	0.25	0.16	减弱	100C>T，3878G>A，4181G>C
*60	0.0	0.14	无	1888-1889insTA
*65		2.95	功能不清	100C>T，2851C>T，4181G>C
*69	0.0	1.00	无	100C>T，2851C>T，2989G>A，4181G>C