CYP2C8, CYP2C9, and CYP2C19 Characterization Using Next-Generation Sequencing and Haplotype Analysis: A GeT-RM Collaborative Project.
CYP2C8, CYP2C9, and CYP2C19 Characterization Using Next-Generation Sequencing and Haplotype Analysis: A GeT-RM Collaborative Project.
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DOI：
10.1016/j.jmoldx.2021.12.011
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发表时间：
2022-04
影响因子：
4.1
通讯作者：
Kalman, Lisa, V
中科院分区：
文献类型：
--
作者：
Gaedigk, Andrea;Boone, Erin C.;Scherer, Steven E.;Lee, Seung-been;Numanagic, Ibrahim;Sahinalp, Cenk;Smith, Joshua D.;McGee, Sean;Radhakrishnan, Aparna;Qin, Xiang;Wang, Wendy Y.;Farrow, Emily G.;Gonzaludo, Nina;Halpern, Aaron L.;Nickerson, Deborah A.;Miller, Neil A.;Pratt, Victoria M.;Kalman, Lisa, V
药物遗传学测试通常靶向选定的序列变体，以鉴定通常由星星（*）等位基因命名法定义的单倍型。由于其设计，这些靶向基因分型检测无法检测可能改变基因产物功能的新变体，从而影响表型预测和患者护理。在本研究中，使用靶向和全基因组测序分析重新表征了先前通过遗传检测参考材料（GeT-RM）程序使用各种靶向基因分型方法表征的137个DNA样本。使用三种基因型调用工具分析序列数据，以鉴定CYP 2C 8、CYP 2C 9和CYP 2C 19的星星等位基因二倍型。来自下一代测序（NGS）的基因型调用与先前报道的基因型调用具有良好的相关性，除非样本中存在新的等位基因。由于靶向基因分型检测未涵盖的变异体的鉴定，在这三个基因中鉴定出6个新等位基因和38个新亚等位基因。此外，使用NGS和/或长读段NGS数据解决了来自先前研究的几个模糊基因型调用。尽管注意到一些差异，但在识别算法之间，二倍体识别大多数是一致的。这项研究强调了NGS在药物遗传学检测中的实用性，并表明即使在高度特征化的基因（如CYP 2C 9和CYP 2C 19）中，仍有许多新的等位基因有待发现。
Pharmacogenetic tests typically target selected sequence variants to identify haplotypes that are often defined by star (*) allele nomenclature. Due to their design, these targeted genotyping assays are unable to detect novel variants that may change the function of the gene product and thereby affect phenotype prediction and patient care. In the current study, 137 DNA samples that were previously characterized by the Genetic Testing Reference Material (GeT-RM) Program using a variety of targeted genotyping methods were recharacterized using targeted and whole genome sequencing analysis. Sequence data were analyzed using three genotype calling tools to identify star allele diplotypes for CYP2C8, CYP2C9 and CYP2C19. The genotype calls from next-generation sequencing (NGS) correlated well to those previously reported, except when novel alleles were present in a sample. Six novel alleles and 38 novel suballeles were identified in the three genes due to identification of variants not covered by targeted genotyping assays. In addition, several ambiguous genotype calls from a previous study were resolved using the NGS and/or long read NGS data. Diplotype calls were mostly consistent between the calling algorithms, although several discrepancies were noted. This study highlights the utility of NGS for pharmacogenetic testing and demonstrates that there are many novel alleles that are yet to be discovered, even in highly characterized genes such as CYP2C9 and CYP2C19.
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影响因子：
12.3
作者：
McLaren W;Gil L;Hunt SE;Riat HS;Ritchie GR;Thormann A;Flicek P;Cunningham F
通讯作者：
Cunningham F
影响因子：
6.7
作者：
Botton MR;Whirl-Carrillo M;Del Tredici AL;Sangkuhl K;Cavallari LH;Agúndez JAG;Duconge J;Lee MTM;Woodahl EL;Claudio-Campos K;Daly AK;Klein TE;Pratt VM;Scott SA;Gaedigk A
通讯作者：
Gaedigk A
影响因子：
5.8
作者：
Li, Heng
通讯作者：
Li, Heng
影响因子：
6.7
作者：
Lee, Seung-been;Wheeler, Marsha M.;Nickerson, Deborah A.
通讯作者：
Nickerson, Deborah A.
影响因子：
4.6
作者：
Loka, Tobias P.;Tausch, Simon H.;Renard, Bernhard Y.
通讯作者：
Renard, Bernhard Y.