Pharmacogenomics and Psychopharmacology

Lapetina, Diego L.; Yang, Esther; Henriques, Beatriz Carvalho; Aitchison, Katherine

doi:10.1017/9781911623465.007

Cited by 2 publications

(3 citation statements)

References 390 publications

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“…Many antidepressants, atomoxetine, and several antipsychotics are metabolized by CYP2D6 and CYP2C19 [1][2][3][4][5][6][7]. The gene (CYP2D6) encoding the enzyme CYP2D6 is on chromosome 22q13.2 [8] adjacent to two pseudogenes, CYP2D7 and CYP2D8 [9,10].…”

Section: Introductionmentioning

confidence: 99%

Methodology for clinical genotyping of CYP2D6 and CYP2C19

Henriques

Buchner

et al. 2021

Transl Psychiatry

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Many antidepressants, atomoxetine, and several antipsychotics are metabolized by the cytochrome P450 enzymes CYP2D6 and CYP2C19, and guidelines for prescribers based on genetic variants exist. Although some laboratories offer such testing, there is no consensus regarding validated methodology for clinical genotyping of CYP2D6 and CYP2C19. The aim of this paper was to cross-validate multiple technologies for genotyping CYP2D6 and CYP2C19 against each other, and to contribute to feasibility for clinical implementation by providing an enhanced range of assay options, customizable automated translation of data into haplotypes, and a workflow algorithm. AmpliChip CYP450 and some TaqMan single nucleotide variant (SNV) and copy number variant (CNV) data in the Genome-based therapeutic drugs for depression (GENDEP) study were used to select 95 samples (out of 853) to represent as broad a range of CYP2D6 and CYP2C19 genotypes as possible. These 95 included a larger range of CYP2D6 hybrid configurations than have previously been reported using inter-technology data. Genotyping techniques employed were: further TaqMan CNV and SNV assays, xTAGv3 Luminex CYP2D6 and CYP2C19, PharmacoScan, the Ion AmpliSeq Pharmacogenomics Panel, and, for samples with CYP2D6 hybrid configurations, long-range polymerase chain reactions (L-PCRs) with Sanger sequencing and Luminex. Agena MassARRAY was also used for CYP2C19. This study has led to the development of a broader range of TaqMan SNV assays, haplotype phasing methodology with TaqMan adaptable for other technologies, a multiplex genotyping method for efficient identification of some hybrid haplotypes, a customizable automated translation of SNV and CNV data into haplotypes, and a clinical workflow algorithm.

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Section: Introductionmentioning

confidence: 99%

Methodology for clinical genotyping of CYP2D6 and CYP2C19

Henriques

Buchner

et al. 2021

Transl Psychiatry

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“…CYP2D6 and CYP2C19 genotyping may thereby become much more readily accessible, with potential substantial savings in health care costs and public benefit. 3 100% of available data (N=24, with no call for one sample) 4 All *1/*2 except one *2/*6 5 *1/*17 6 All *2/*17 with one *2.002/*17 7 One *2/*2.002 Table 2. Comparative CYP2D6 data for samples with a CNV call of 1, with pairwise interplatform concordance…”

Section: Resultsmentioning

confidence: 99%

“…antipsychotics (e.g., aripiprazole, risperidone, haloperidol, zuclopenthixol, and pimozide), antiarrhythmics (e.g., flecainide and propafenone), beta-blockers (e.g., metoprolol and propranolol), opioids (e.g., codeine), antiemetics (e.g., metoclopramide and ondansetron), antitussives (e.g., dextromethorphan) and anticancer agents such as the hormonal modulator tamoxifen. [2][3][4][5] Substrates for CYP2C19 include proton pump inhibitors (omeprazole and pantoprazole), the antithrombotic clopidogrel, antidepressants (fluoxetine, sertraline, paroxetine, citalopram, escitalopram, moclobemide, imipramine, amitriptyline, clomipramine), antipsychotics (e.g., clozapine and olanzapine), anxiolytics (diazepam and propranolol), the anticonvulsant phenytoin, and immunologically active agents (e.g., cyclophosphamide, nelfinavir, proguanil, and voriconazole). 5 The gene (CYP2D6) encoding the enzyme CYP2D6 is on chromosome 22q13.2 6 adjacent to two pseudogenes, CYP2D7 and CYP2D8 .…”

Section: Introductionmentioning

confidence: 99%

Cross-validation of technologies for genotypingCYP2D6andCYP2C19

Aitchison

Henriques

Yavorskyy

et al. 2019

Preprint

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AbstractBackgroundCYP2D6 and CYP2C19 are cytochrome P450 enzymes involved in the metabolism of many medications from multiple therapeutic classes. The genes encoding them, CYP2D6 and CYP2C19, have multiple functional variants that have been associated with different levels of enzyme activity. There is evidence that methodology for identifying such variants (“genotyping”) effectively and efficiently could lead to substantial health care costs savings. There are various genotyping technologies available; we cross-validated several against each other.MethodsNinety-six samples with a variety of CYP2D6 and CYP2C19 genotypes according to prior AmpliChip CYP450 and TaqMan CYP2C19*17 data were selected from the Genome-based therapeutic drugs for depression (GENDEP) study. Genotyping was performed with TaqMan copy number variant (CNV) analysis using probes specific for three different regions (CYP2D6 only), the next generation sequencing-based Ion S5 AmpliSeq Pharmacogenomics Panel, PharmacoScan, and long-range polymerase chain reaction (XL-PCR) followed by TaqMan single nucleotide variant (SNV) analysis or the Agena MassARRAY. Variant to “star allele” translation was automated.ResultsThe inter-platform concordance for CYP2C19 was high (94-98%). For CYP2D6, the IonS5-PharmacoScan concordance was 94% for a range of variants tested apart from those with at least one extra copy of a CYP2D6 gene (occurring at a frequency of 3.8%, 33/853), or a pseudogene-gene conversion (2%, 18/853).ConclusionsInter-platform concordance for CYP2C19 was high, and, moreover, the Ion S5 and PharmacoScan data were 100% concordant with that from a TaqMan CYP2C19*2 assay. The level of concordance was also good for CYP2D6, apart from those with at least one extra copy of a CYP2D6 gene or a pseudogene-gene conversion. We have also demonstrated feasibility of using a NGS platform for genotyping CYP2D6 and CYP2C19, with automated data interpretation methodology. CYP2D6 and CYP2C19 genotyping may thereby become much more readily accessible, with potential substantial savings in health care costs and public benefit.

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Pharmacogenomics and Psychopharmacology

Cited by 2 publications

References 390 publications

Methodology for clinical genotyping of CYP2D6 and CYP2C19

Methodology for clinical genotyping of CYP2D6 and CYP2C19

Cross-validation of technologies for genotypingCYP2D6andCYP2C19

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