<i>CYP2D6</i> allele frequencies, copy number variants, and tandems in the population of Hong Kong

Chan, Wing Lee; Li, Man S.; Sundaram, Senthilarasu; Tomlinson, Brian; Cheung, Pik Yuen Belinda; Tzang, Chi-Hung

doi:10.1002/jcla.22634

Cited by 22 publications

(23 citation statements)

References 30 publications

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“…The frequency of each actionable phenotype was derived from the allele frequency of the Hong Kong Chinese exome dataset based on the Hardy-Weinberg equation, except for CYP2D6 . The frequency of actionable phenotype of CYP2D6 was retrieved from a published Hong Kong study, since exome sequencing cannot detect haplotype and copy number variations accurately [ 27 ]. The projected prescription impact for each drug was estimated by multiplying the frequency of actionable phenotype by the total number of subjects for each individual drug retrieved from CDARS.…”

Section: Methodsmentioning

confidence: 99%

Actionable pharmacogenetic variants in Hong Kong Chinese exome sequencing data and projected prescription impact in the Hong Kong population

Chan

Chung

et al. 2021

PLoS Genet

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Preemptive pharmacogenetic testing has the potential to improve drug dosing by providing point-of-care patient genotype information. Nonetheless, its implementation in the Chinese population is limited by the lack of population-wide data. In this study, secondary analysis of exome sequencing data was conducted to study pharmacogenomics in 1116 Hong Kong Chinese. We aimed to identify the spectrum of actionable pharmacogenetic variants and rare, predicted deleterious variants that are potentially actionable in Hong Kong Chinese, and to estimate the proportion of dispensed drugs that may potentially benefit from genotype-guided prescription. The projected preemptive pharmacogenetic testing prescription impact was evaluated based on the patient prescription data of the public healthcare system in 2019, serving 7.5 million people. Twenty-nine actionable pharmacogenetic variants/ alleles were identified in our cohort. Nearly all (99.6%) subjects carried at least one actionable pharmacogenetic variant, whereas 93.5% of subjects harbored at least one rare deleterious pharmacogenetic variant. Based on the prescription data in 2019, 13.4% of the Hong Kong population was prescribed with drugs with pharmacogenetic clinical practice guideline recommendations. The total expenditure on actionable drugs was 33,520,000 USD, and it was estimated that 8,219,000 USD (24.5%) worth of drugs were prescribed to patients with an implicated actionable phenotype. Secondary use of exome sequencing data for pharmacogenetic analysis is feasible, and preemptive pharmacogenetic testing has the potential to support prescription decisions in the Hong Kong Chinese population.

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Section: Methodsmentioning

confidence: 99%

Actionable pharmacogenetic variants in Hong Kong Chinese exome sequencing data and projected prescription impact in the Hong Kong population

Chan

Chung

et al. 2021

PLoS Genet

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“…While we report similar frequencies for CYP2D6 deletion or duplication alleles as in PharmGKB, we report a higher frequency than PharmGKB for the SV-containing haplotype *36 + *10 in East-Asians and another SV *68 + *4 in Europeans (Figure 5B, red annotated dots). Previously reported frequencies of *36 + *10 in East-Asians fall into a wide range (10-35%) 32–37 , indicating the variability in CNV testing across assays. Additionally, *68 is often not interrogated in many studies, and it has been suggested that >20% of reported *4 alleles are actually in tandem with *68 38,39 .…”

Section: Resultsmentioning

confidence: 93%

Cyrius: accurateCYP2D6genotyping using whole genome sequencing data

Chen

Shen

Gonzaludo

et al. 2020

Preprint

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Responsible for the metabolism of 25% of all drugs, CYP2D6 is a critical component of personalized medicine initiatives. Genotyping CYP2D6 is challenging due to sequence similarity with its pseudogene paralog CYP2D7 and a high number and variety of common structural variants (SVs). Here we describe a novel bioinformatics method, Cyrius, that accurately genotypes CYP2D6 using whole-genome sequencing (WGS) data. Using a validation data set consisting of reference samples with diverse genotypes as well as PacBio long read data, we show that Cyrius has superior performance (96.5% concordance with truth genotypes) compared to existing methods (83.8-86.6%). After implementing the improvements identified from the comparison against the truth data, Cyrius's accuracy has since been improved to 99.3%. Using Cyrius, we built a haplotype frequency database from 2504 ethnically diverse samples and estimate that SV-containing star alleles are more frequent than previously reported. Cyrius will be a useful tool for pharmacogenomics applications with WGS and help bring the promise of precision medicine one step closer to reality. Running Aldy and StargazerAldy v2.2.5 was run using the command "aldy genotype -p illumina -g CYP2D6".Stargazer v1.0.7 was run to genotype CYP2D6 using VDR as the control gene, with GDF and VCF files as input.The 1kGP GeT-RM samples were originally aligned against hg38. As Aldy and Stargazer only support GRCh37, for comparison between methods, these samples were realigned against GRCh37 using Isaac 26 .

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“…Variation in CYP2D6 includes single-nucleotide variants (SNVs), indels, whole-gene deletions, multiplications, tandem arrangements and hybridisations [40,44]; it can also be affected by larger chromosomal deletions or other structural alterations as part of the rare 22q13 deletion syndrome, known as Phelan-McDermid syndrome. Currently, there are 133 CYP2D6 "star" ("*") alleles listed on the PharmVar data repository [45], as detailed within a recent and in-depth review of 2D6 nomenclature and 2D6 allele designation by Nofziger et al [46].…”

Section: An Overview Of Cyp2d6 Variationmentioning

confidence: 99%

“…The significance of this type of variation on the metaboliser phenotype of CYP2D6 depends on the functionality of the duplicated CYP2D6 allele. Indeed, it has been shown in a population of patients from Hong Kong that fewer than 20% of duplicated CYP2D6 alleles were duplications of functional alleles [44]. However, an increased copy number of functional CYP2D6 alleles increases the rate of metabolism of associated drugs [39], with some studies reporting as many as 13 copies of CYP2D6 in a single individual's genome [48].…”

Section: Copy Number Variationmentioning

confidence: 99%

“…In most tandems, at least one gene copy is a CYP2D7-2D6 or CYP2D6-2D7 hybrid arrangement. CYP2D6*36 + *10 is the most common tandem arrangement, and is particularly prominent in East Asian populations with an MAF of 34.1% [44]. In this tandem arrangement, the 5 upstream gene unit is usually a 2D6-2D7 hybrid (*36), whilst the 3 downstream gene unit contains the missense SNP that defines *10 (rs1065852, p.P34S).…”

Section: Hybridisations Tandem Arrangements and Conversionsmentioning

confidence: 99%

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A Review of the Important Role of CYP2D6 in Pharmacogenomics

Taylor

Crosby²,

Yip

et al. 2020

Genes

150

101

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Cytochrome P450 2D6 (CYP2D6) is a critical pharmacogene involved in the metabolism of ~20% of commonly used drugs across a broad spectrum of medical disciplines including psychiatry, pain management, oncology and cardiology. Nevertheless, CYP2D6 is highly polymorphic with single-nucleotide polymorphisms, small insertions/deletions and larger structural variants including multiplications, deletions, tandem arrangements, and hybridisations with non-functional CYP2D7 pseudogenes. The frequency of these variants differs across populations, and they significantly influence the drug-metabolising enzymatic function of CYP2D6. Importantly, altered CYP2D6 function has been associated with both adverse drug reactions and reduced drug efficacy, and there is growing recognition of the clinical and economic burdens associated with suboptimal drug utilisation. To date, pharmacogenomic clinical guidelines for at least 48 CYP2D6-substrate drugs have been developed by prominent pharmacogenomics societies, which contain therapeutic recommendations based on CYP2D6-predicted categories of metaboliser phenotype. Novel algorithms to interpret CYP2D6 function from sequencing data that consider structural variants, and machine learning approaches to characterise the functional impact of novel variants, are being developed. However, CYP2D6 genotyping is yet to be implemented broadly into clinical practice, and so further effort and initiatives are required to overcome the implementation challenges and deliver the potential benefits to the bedside.

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CYP2D6 allele frequencies, copy number variants, and tandems in the population of Hong Kong

Abstract: The present study provides a comprehensive analysis on the occurrences of CNV and tandems of the CYP2D6 gene in the Hong Kong population. The results contribute to the overall knowledge of pharmacogenomics and may accelerate the implementation of precision medicine in Asia.

Cited by 22 publications

References 30 publications

Actionable pharmacogenetic variants in Hong Kong Chinese exome sequencing data and projected prescription impact in the Hong Kong population

Actionable pharmacogenetic variants in Hong Kong Chinese exome sequencing data and projected prescription impact in the Hong Kong population

Cyrius: accurateCYP2D6genotyping using whole genome sequencing data

A Review of the Important Role of CYP2D6 in Pharmacogenomics

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