College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia.
Neuropsychiatric Laboratory, South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
J Psychopharmacol. 2024 Sep;38(9):771-783. doi: 10.1177/02698811241268899. Epub 2024 Sep 11.
The enzyme expression (i.e. phenotype) of the Cytochrome P450 2D6 (CYP2D6) gene is highly relevant to the metabolism of psychotropic medications, and therefore to precision medicine (i.e. personalised prescribing).
This review aims to assess the improvement in CYP2D6 phenotyping sensitivity (IPS) and accuracy (IPA) offered by long-read sequencing (LRS), a new genetic testing technology.
Human DNA samples that underwent LRS genotyping of CYP2D6 in published, peer-reviewed clinical research were eligible for inclusion. A systematic literature search was conducted until 30 September 2023. CYP2D6 genotypes were translated into phenotypes using the international consensus method. IPS was the percentage of non-normal LRS CYP2D6 phenotypes undetectable with FDA-approved testing (AmpliChip). IPA was the percentage of LRS CYP2D6 phenotypes mischaracterised by non-LRS genetic tests (for samples with LRS and non-LRS data).
Six studies and 1411 samples were included. In a meta-analysis of four studies, IPS was 10% overall (95% CI = (2, 18); = 1385), 20% amongst Oceanians (95% CI = (17, 23); = 582) and 2% amongst Europeans (95% CI = (1, 4); = 803). IPA was 4% in a large European cohort (95% CI = (2, 7); = 567). When LRS was used selectively (e.g. for novel or complex CYP2D6 genotypes), very high figures were observed for IPS (e.g. 88%; 95% CI = (72, 100); = 17; country = Japan) and IPA (e.g. 76%; 95% CI = (55, 98); = 17; country = Japan).
LRS improves CYP2D6 phenotyping compared to established genetic tests, particularly amongst Oceanian and Japanese individuals, and those with novel or complex genotypes. LRS may therefore assist in optimising personalised prescribing of psychotropic medications. Further research is needed to determine associated clinical benefits, such as increased medication safety and efficacy.
细胞色素 P450 2D6（CYP2D6）基因的酶表达（即表型）与精神药物的代谢密切相关，因此与精准医学（即个体化处方）相关。
本综述旨在评估长读测序（LRS）这种新的基因检测技术对 CYP2D6 表型灵敏度（IPS）和准确性（IPA）的改善。
符合条件的研究为已发表的同行评议临床研究中接受 LRS 基因分型 CYP2D6 的人类 DNA 样本。系统文献检索截止到 2023 年 9 月 30 日。使用国际共识方法将 CYP2D6 基因型转化为表型。IPS 是指 FDA 批准的检测无法检测到的非正常 LRS CYP2D6 表型的百分比（AmpliChip）。IPA 是指非 LRS 遗传检测错误标记的 LRS CYP2D6 表型的百分比（对于具有 LRS 和非 LRS 数据的样本）。
共纳入 6 项研究和 1411 个样本。四项研究的荟萃分析显示，IPS 总体为 10%（95%CI=（2，18）；=1385），大洋洲人群为 20%（95%CI=（17，23）；=582），欧洲人群为 2%（95%CI=（1，4）；=803）。在一个大型欧洲队列中，IPA 为 4%（95%CI=（2，7）；=567）。当 LRS 被选择性使用时（例如，用于新型或复杂的 CYP2D6 基因型），IPS 非常高（例如 88%（95%CI=（72，100）；=17；国家=日本）和 IPA（例如 76%（95%CI=（55，98）；=17；国家=日本）。
与现有遗传检测相比，LRS 提高了 CYP2D6 表型，特别是在大洋洲和日本人群中，以及新型或复杂基因型人群中。因此，LRS 可能有助于优化精神药物的个体化处方。需要进一步研究以确定相关的临床获益，例如提高药物安全性和疗效。
