Cross-validation of technologies for genotyping CYP2D6 and CYP2C19
Beatriz Carvalho Henriques,
Bahareh Behroozi Asl,
Mojca Z Dernovsek,
Marcella D.C. Rietschel,
Katherine J. Aitchison
Posted 26 Dec 2019
bioRxiv DOI: 10.1101/2019.12.24.870295
Posted 26 Dec 2019
Background: CYP2D6 and CYP2C19 are cytochrome P450 enzymes involved in the metabolism of many medications from multiple therapeutic classes. Associations between patterns of variants (known as haplotypes) in the genes encoding them (CYP2D6 and CYP2C19) and enzyme activities are well described. The genes in fact comprise 21% of biomarkers in drug labels. Despite this, genotyping is not common, partly attributable to its challenging nature (CYP2D6 having >100 haplotypes, including those with sequence from an adjacent pseudogene, and gene duplications). We cross-validated different methodologies for identifying haplotypes in these genes against each other. Methods: Ninety-two 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) and single nucleotide variant (SNV) analysis, the next generation sequencing-based Ion S5 AmpliSeq Pharmacogenomics Panel, PharmacoScan, long-range polymerase chain reaction (L-PCR) followed by amplicon analysis, and Agena for CYP2C19. Variant pattern to haplotype translation was automated. Results: The inter-platform concordance for CYP2C19 was high (up to 100% for available data). 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 those with substantial sequence derived from pseudogene, known as hybrids (3%, 26/853). Conclusions: Inter-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. We have also demonstrated feasibility of using an NGS platform for genotyping CYP2D6 and CYP2C19, with automated data interpretation methodology. This points the way to a method of making CYP2D6 and CYP2C19 genotyping more readily accessible. ### Competing Interest Statement N.H. has participated in research supported by CSF project No. IP-09-2014-2979. D.S. has received grant/research support from Janssen and Lundbeck, and has served as a consultant or on advisory boards for Janssen and Lundbeck. C.A.B. is a member of the Clinical Pharmacogenetics Implementation Consortium and the Pharmacogene Variation Consortium; he has also participated in collaborative research with employees of MyDNA (a pharmacogenetic testing company) but does not have equity, stocks, or options in this company or any other pharmacogenetic companies. K.J.A. is a member of the Clinical Pharmacogenetics Implementation Consortium and the Pharmacogene Variation Consortium, has received two research grants in the last two years from Janssen Inc., Canada (fellowship grants for trainees) and provided consultancy services (unpaid) for HLS Therapeutics. All other authors have nothing to disclose.
- Downloaded 621 times
- Download rankings, all-time:
- Site-wide: 33,275 out of 118,129
- In genetics: 1,706 out of 5,131
- Year to date:
- Site-wide: 12,330 out of 118,129
- Since beginning of last month:
- Site-wide: 11,767 out of 118,129
Downloads over time
Distribution of downloads per paper, site-wide
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!