大型回顾性研究中 CYP2D6 结构变异的普遍性。

IF 1.7 3区 医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Pharmacogenetics and genomics Pub Date : 2024-06-01 Epub Date: 2024-02-19 DOI:10.1097/FPC.0000000000000525
Samantha Frear, Ashley Sherman, Don Rule, Lauren Ann Marcath
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引用次数: 0

摘要

CYP2D6 是一种高度多态的基因,其结构变异在临床上具有重要意义。临床药理基因组学研究通常只检测外显子 9,因为即使存在 CYP2D6::CYP2D7 转换,也能准确地确定其功能特征。然而,这种方法不能捕获 CYP2D7::CYP2D6(CYP2D6*13)转换,可能导致表型分配不准确。本研究的目的是利用多个拷贝数变异(CNV)检测位置确定 CYP2D6 结构变异的频率,以量化其对临床表型分类的潜在影响。我们对通过 Translational Software, Inc.平台提交的去标识化药物基因组学数据进行了回顾性分析。研究纳入了外显子 9 和至少一个额外 CNV 位置(5'UTR、外显子 1、内含子 2、外显子 5 或内含子 6)的 CYP2D6 CNV 数据样本。CYP2D7::CYP2D6 和 CYP2D6::CYP2D7 转换根据 PharmVar 术语进行分类。CYP2D6 的总拷贝数以 4 个拷贝为上限,以考虑到检测超过 4 个拷贝时检测方法的局限性。共纳入 106,474 份样本进行分析。约 2.44% 的样本存在 CYP2D7::CYP2D6 转换,5.84% 的样本存在 CYP2D6::CYP2D7 转换。许多样本没有检测到 CYP2D7 转换(91.5%;97,462/106,474)。0.15%的样本检测到全基因缺失,5.98%的样本存在重复或倍增。这项回顾性研究强调了检测一个以上 CYP2D6 CNV 位点的重要性。超过 2% 的患者被发现有 CYP2D7::CYP2D6 转换。这可能导致表型分类错误和临床建议不一致。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Prevalence of CYP2D6 structural variation in large retrospective study.

CYP2D6 is a highly polymorphic gene with clinically important structural variations. Commonly, only exon 9 is assayed on clinical pharmacogenomics panels, as it allows for accurate functional characterization even in the presence of a CYP2D6::CYP2D7 conversion. However, this method does not capture CYP2D7::CYP2D6 (CYP2D6*13) conversions, possibly leading to inaccurate phenotype assignment. The study's purpose was to determine the frequency of structural variations in CYP2D6 utilizing multiple copy number variation (CNV) assay locations to quantify the potential impact on clinical phenotype classification. A retrospective analysis was conducted of de-identified pharmacogenomics data submitted through the Translational Software, Inc. platform. Samples with CYP2D6 CNV data for exon 9 and at least one additional CNV location (5'UTR, exon 1, intron 2, exon 5 or intron 6) were included. CYP2D7::CYP2D6 and CYP2D6::CYP2D7 conversions were classified according to PharmVar nomenclature. The CYP2D6 copies were capped at four total copies to account for assay limitations in detecting more than four copies. A total of 106,474 samples were included for analysis. CYP2D7::CYP2D6 conversions were present in approximately 2.44% of samples, and 5.84% of samples had CYP2D6::CYP2D7 conversions. Many samples did not have a CYP2D7 conversion detected (91.5%; 97,462/106,474). A full gene deletion was detected in 0.15%, and 5.98% had a duplication or multiplication present. This retrospective study underscores the importance of testing more than one CNV site for CYP2D6 . Over 2% of patients were found to have a CYP2D7::CYP2D6 conversion. This translates into potentially misclassified phenotype classification and incongruent clinical recommendations.

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来源期刊
Pharmacogenetics and genomics
Pharmacogenetics and genomics 医学-生物工程与应用微生物
CiteScore
3.20
自引率
3.80%
发文量
47
审稿时长
3 months
期刊介绍: ​​​​Pharmacogenetics and Genomics is devoted to the rapid publication of research papers, brief review articles and short communications on genetic determinants in response to drugs and other chemicals in humans and animals. The Journal brings together papers from the entire spectrum of biomedical research and science, including biochemistry, bioinformatics, clinical pharmacology, clinical pharmacy, epidemiology, genetics, genomics, molecular biology, pharmacology, pharmaceutical sciences, and toxicology. Under a single cover, the Journal provides a forum for all aspects of the genetics and genomics of host response to exogenous chemicals: from the gene to the clinic.
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