PharmVar GeneFocus: <i>CYP2D6</i>

Nofziger, Charity; Turner, Amy; Sangkuhl, Katrin; Whirl‐Carrillo, Michelle; Agúndez, José A.G.; Black, John L.; Dunnenberger, Henry M.; Ruaño, Gualberto; Kennedy, Martin A.; Phillips, Michael; Hachad, Houda; Klein, Teri E.; Gaedigk, Andrea

doi:10.1002/cpt.1643

Cited by 183 publications

(216 citation statements)

References 96 publications

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“…3,4 The CYP2D6 gene is notoriously difficult to interrogate, 5 however, due to challenges imposed by the complexity of the CYP2D gene locus, which includes a highly homologous pseudogene, CYP2D7, and a high degree of CYP2D6 variation. 3,[6][7][8] Due to such variation, targeted genotyping panels may miss rare, clinically relevant variants that are present in an individual but not interrogated, leading to phenotype misclassification. 3,7 This is particularly problematic in diverse populations where there are limited or no data regarding genetic variation.…”

Section: Cyp2d6 Structural Variants and Phenotype Predictionmentioning

confidence: 99%

Interrogation of CYP2D6 Structural Variant Alleles Improves the Correlation Between CYP2D6 Genotype and CYP2D6‐Mediated Metabolic Activity

Dalton

Lee

Claw

et al. 2019

Clinical Translational Sci

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The cytochrome P450 2D6 (CYP2D6) gene locus is challenging to accurately genotype due to numerous single nucleotide variants and complex structural variation. Our goal was to determine whether the CYP2D6 genotype‐phenotype correlation is improved when diplotype assignments incorporate structural variation, identified by the bioinformatics tool Stargazer, with next‐generation sequencing data. Using CYP2D6 activity measured with substrates dextromethorphan and metoprolol, activity score explained 40% and 34% of variability in metabolite formation rates, respectively, when diplotype calls incorporated structural variation, increasing from 36% and 31%, respectively, when diplotypes did not incorporate structural variation. We also investigated whether the revised Clinical Pharmacogenetics Implementation Consortium (CPIC) recommendations for translating genotype to phenotype improve CYP2D6 activity predictions over the current system. Although the revised recommendations do not improve the correlation between activity score and CYP2D6 activity, perhaps because of low frequency of the CYP2D6*10 allele, the correlation with metabolizer phenotype group was significantly improved for both substrates. We also measured the function of seven rare coding variants: one (A449D) exhibited decreased (44%) and another (R474Q) increased (127%) activity compared with reference CYP2D6.1 protein. Allele‐specific analysis found that A449D is part of a novel CYP2D6*4 suballele, CYP2D6*4.028. The novel haplotype containing R474Q was designated CYP2D6*138 by PharmVar; another novel haplotype containing R365H was designated CYP2D6*139. Accuracy of CYP2D6 phenotype prediction is improved when the CYP2D6 gene locus is interrogated using next‐generation sequencing coupled with structural variation analysis. Additionally, revised CPIC genotype to phenotype translation recommendations provides an improvement in assigning CYP2D6 activity.

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Section: Cyp2d6 Structural Variants and Phenotype Predictionmentioning

confidence: 99%

Interrogation of CYP2D6 Structural Variant Alleles Improves the Correlation Between CYP2D6 Genotype and CYP2D6‐Mediated Metabolic Activity

Dalton

Lee

Claw

et al. 2019

Clinical Translational Sci

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“…Although the CYP2D6*2 allele is generally considered to be an allele of CYP2D6 normal enzyme activity, the multiple mutation loci making up CYP2D6*2 contain the mutation at c. 886 locus which has the effect of reducing the activity of CYP2D6 enzyme [39][40]. Therefore, this study may further support the complexity of CYP2D6*2 allele effect on CYP2D6 enzyme activity change [39][40][44][45].…”

Section: Sample Information and Pcr Ampli Cation Of Human Cyp2d6 Genementioning

confidence: 68%

“…Such very different results might be attributed to the different subjects chosen between two studies, the subjects in this study were vivax malaria cases who mainly settled in the traditional malaria endemic areas in Yunnan Province, and the long-term malaria epidemic is thought to result in positive screening on human defective genes [41][42][43]. Moreover, in this study all of alleles were identi ed only based on the mutations of CYP2D6 gene exon regions, but it is still different from the allelic recognition including intron mutations [33,44]. Therefore, the homogeneity of CYP2D6*2 allele in the two studies may be the reason why the results between research display different.…”

Section: Sample Information and Pcr Ampli Cation Of Human Cyp2d6 Genementioning

confidence: 99%

Genetic Polymorphism of Cyp2d6 Gene Coding Region and Association Between Them With Vivax Malaria Relapse in Yunnan Province, China

Huang

Duan

et al. 2020

Preprint

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BackgroundPrimaquine is one of two medications able to effectively eliminate the hypnozoites of P. vivax, and therefore has been recommended by World Health Organization (WHO) as the anti-relapsing drug for vivax malaria patients. However, the reduced CYP2D6 enzyme activity caused by gene mutations has been considered to result in the failure of primaquine relapse vivax malaria. Based on the analysis of CYP2D6 gene polymorphisms in vivax malaria cases the current study aims to determine the association between human CYP2D6 polymorphism and the relapse of vivax malaria. MethodsBlood samples of vivax malaria cases who received "chloroquine/primaquine eight-day therapy" from 2014 to 2018 in Yunnan Province were collected. The suspected relapsed cases were determined by epidemiology and gene sequence alignment. Human genomic DNA was extracted from the blood samples, nine exons of CYP2D6 gene were amplified by polymerase chain reaction (PCR) and PCR products were then sequenced. The coding DNA sequence (CDS) of CYP2D6 gene was obtained by splicing and aligning with the non-mutation reference sequence. The mutation loci, haplotypes (star alleles) and genotypes of CYP2D6 gene were inferred and their association with vivax malaria relapse were analyzed. ResultsA total of 120 blood samples from 45 suspected relapsed cases of vivax malaria and 75 non-relapsed cases were collected and two nested-PCR products (2411bp and 2388bp) containing exon1-4 and exon5-9, were obtained from 119 samples. 119 CDS chains (1491bp length) were formed by splicing and combining sequencing sequences, A total of 12 mutation loci were identified in 238 CDS chains (including 119 chains from direct sequencing and another 119 chains identified from sister chromosome). Among them, the mutation locus at c.886 has the closest relationship with the relapse of vivax malaria (OR=2.167, 95%CI: 1.104~4.252, P<0.05). There were 23 haplotypes (Hap_1~Hap_23) to be identified and be defined as 23 alleles of CYP2D6 gene, Among them, the 5 star alleles (*1, *2, *4, *10 and *39) were confirmed by comparison, and the CYP2D6*10 allele accounted for the most (45.4%, 108/238). the frequency of CYP2D6*2 allele in the SR group was significantly higher than that in the NR group (P<0.05). However, among the defined 24 genotypes, there were 8 genotypes (*4/*4, *4/*o, *2/*39, *39/*m, *39/*x, *1/*r, *1/*n, and *v/*10) appeared only in the SR group.ConclusionAmong the numerous mutations of CYP2D6 gene，CYP2D6*10 allele accounts for the highest proportion of vivax malaria cases in Yunnan Province. The mutation at c. 886 locus is most closely related to the relapse of vivax malaria. In addition, there was the genotype *4/*4 with null CYP2D6 enzyme function. These results suggest that Yunnan Province should pay attention to the risk of reduced CYP2D6 enzyme activity on the radical cure therapeutic effect of primaquine

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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]. In essence, the star allele nomenclature system represents a useful haplotype-based system that is well established and recognised within the pharmacogenomic field [46].…”

Section: An Overview Of Cyp2d6 Variationmentioning

confidence: 99%

“…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]. In essence, the star allele nomenclature system represents a useful haplotype-based system that is well established and recognised within the pharmacogenomic field [46]. Many of the listed variants contribute in part or entirely to altered rates of CYP2D6-associated drug metabolism.…”

Section: An Overview Of Cyp2d6 Variationmentioning

confidence: 99%

A Review of the Important Role of CYP2D6 in Pharmacogenomics

Taylor

Crosby²,

Yip

et al. 2020

Genes

168

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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PharmVar GeneFocus: CYP2D6

Abstract: As of September 2019 there are 131 CYP2D6 core allele definitions (1 through 139, eight alleles have been retired). a Evidence levels for these alleles were revised from "Lim" (Limited) or "Mod" (Moderate) to "Def" (Definitive).

Cited by 183 publications

References 96 publications

Interrogation of CYP2D6 Structural Variant Alleles Improves the Correlation Between CYP2D6 Genotype and CYP2D6‐Mediated Metabolic Activity

Interrogation of CYP2D6 Structural Variant Alleles Improves the Correlation Between CYP2D6 Genotype and CYP2D6‐Mediated Metabolic Activity

Genetic Polymorphism of Cyp2d6 Gene Coding Region and Association Between Them With Vivax Malaria Relapse in Yunnan Province, China

A Review of the Important Role of CYP2D6 in Pharmacogenomics

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PharmVar GeneFocus: CYP2D6

Abstract: As of September 2019 there are 131 CYP2D6 core allele definitions (*1 through *139, eight alleles have been retired). a Evidence levels for these alleles were revised from "Lim" (Limited) or "Mod" (Moderate) to "Def" (Definitive).

Cited by 183 publications

References 96 publications

Interrogation of CYP2D6 Structural Variant Alleles Improves the Correlation Between CYP2D6 Genotype and CYP2D6‐Mediated Metabolic Activity

Interrogation of CYP2D6 Structural Variant Alleles Improves the Correlation Between CYP2D6 Genotype and CYP2D6‐Mediated Metabolic Activity

Genetic Polymorphism of Cyp2d6 Gene Coding Region and Association Between Them With Vivax Malaria Relapse in Yunnan Province, China

A Review of the Important Role of CYP2D6 in Pharmacogenomics

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Product

Resources

About

Abstract: As of September 2019 there are 131 CYP2D6 core allele definitions (1 through 139, eight alleles have been retired). a Evidence levels for these alleles were revised from "Lim" (Limited) or "Mod" (Moderate) to "Def" (Definitive).