Interrogation of <i><scp>CYP</scp>2D6</i> Structural Variant Alleles Improves the Correlation Between <i><scp>CYP</scp>2D6</i> Genotype and <scp>CYP</scp>2D6‐Mediated Metabolic Activity

Dalton, Rachel; Lee, Seung‐been; Claw, Katrina G.; Prasad, Bhagwat; Phillips, Brian; Shen, Danny D.; Wong, Lai Hong; Fade, Mitch; McDonald, Matthew; Dunham, Maitreya J.; Fowler, Douglas M.; Rettie, Allan E.; Schuetz, Erin G.; Thornton, Timothy A.; Nickerson, Deborah A.; Gaedigk, Andrea; Thummel, Kenneth E.; Woodahl, Erica L.

doi:10.1111/cts.12695

Cited by 44 publications

(21 citation statements)

References 46 publications

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“…Furthermore, an AS of 1 is no longer categorized as NM, but as IM. While the new system has recently been applied to an in vitro study comprising mostly Caucasian liver tissue samples 20 , there are no investigations to date assessing the performance of the new method on any Asian populations with high frequencies of CYP2D6*10 . There is also a paucity of information regarding the impact of substrate specificity on performance of the new translation method.…”

Section: Introductionmentioning

confidence: 99%

Relationship between CYP2D6 genotype, activity score and phenotype in a pediatric Thai population treated with risperidone

Hongkaew

Gaedigk

Wilffert

et al. 2021

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Recently, the Clinical Pharmacogenetics Implementation Consortium (CPIC) have revised recommendations for the translation of CYP2D6 genotype to phenotype. Changes affect phenotype grouping, as well as the value used to calculate activity score for the CYP2D6*10 allele to better reflect the substantially decreased activity of this allele which is the most frequent allele found in Asian populations. This study aimed to evaluate whether the lower value for CYP2D6*10 as recommended, and the revised phenotype groupings improve the relationship between CYP2D6 genotype and risperidone measures. One hundred and ninety-nine children and adolescents with autism treated with a risperidone-based regimen for at least four weeks were included. CYP2D6 genotype was determined using the Luminex xTAG CYP2D6 Kit assay and translated into phenotype using different translation methods. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured using LC/MS/MS. Plasma levels of risperidone, risperidone concentration/dose ratio, and risperidone/9-hydroxyrisperidone ratio in patients with an activity score < 1 were significantly higher than those ≥ 1 (P value < 0.001 for all three parameters). Plasma risperidone levels and risperidone concentration/dose ratios were significantly higher in intermediate metabolizers (defined as AS = 0.25–0.75) than normal metabolizer (defined as AS = 1–2) patients (1.44 vs. 0.23 ng/ml, P < 0.001 and 1.63 vs. 0.29 ng/ml/ng, P < 0.001, respectively) as well as risperidone/9-hydroxyrisperidone ratio (0.20 vs. 0.04, P < 0.001). This is the first study in an Asian population utilizing the revised CPIC-recommended method for translating the CYP2D6 genotype to phenotype. In addition to validating that CYP2D6 genetic variation significantly impacts risperidone metabolism, we demonstrated that revised value for the CYP2D6*10 was superior for genotype to phenotype translation. However, at least for risperidone, subjects with an activity score of 1 presented as phenotypic normal, and not intermediate metabolizers, suggesting that phenotype classification is substrate dependent.

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Section: Introductionmentioning

confidence: 99%

Relationship between CYP2D6 genotype, activity score and phenotype in a pediatric Thai population treated with risperidone

Hongkaew

Gaedigk

Wilffert

et al. 2021

Sci Rep

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“…This model predicted the activity score of an additional set of 10,000 simulated pairs of star alleles with 100% accuracy. The weights from the convolutional layers were then transferred to a new network, which was trained to predict the measured metabolic function for a CYP2D6 substrate, dextromethorphan, in 249 liver microsomes[ 36 ], a regression problem. This model explained 61% of the variance in the training data and 70% of the variance in a held-out set of 59 samples.…”

Section: Resultsmentioning

confidence: 99%

“…We simulate diplotypes rather than haplotypes in order to be able to further train the model using functional activity data collected from liver microsomes. In the second stage of training, a regression model was trained to predict measured metabolic activity of 314 liver microsome samples using dextromethorphan as substrate[ 36 ]. The weights derived from the convolutional layers of the first model were transferred to the second model and the fully connected portion of the model was retrained using randomly initialized weights.…”

Section: Methodsmentioning

confidence: 99%

Transfer learning enables prediction of CYP2D6 haplotype function

et al. 2020

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Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic gene whose protein product metabolizes more than 20% of clinically used drugs. Genetic variations in CYP2D6 are responsible for interindividual heterogeneity in drug response that can lead to drug toxicity and ineffective treatment, making CYP2D6 one of the most important pharmacogenes. Prediction of CYP2D6 phenotype relies on curation of literature-derived functional studies to assign a functional status to CYP2D6 haplotypes. As the number of large-scale sequencing efforts grows, new haplotypes continue to be discovered, and assignment of function is challenging to maintain. To address this challenge, we have trained a convolutional neural network to predict functional status of CYP2D6 haplotypes, called Hubble.2D6. Hubble.2D6 predicts haplotype function from sequence data and was trained using two pre-training steps with a combination of real and simulated data. We find that Hubble.2D6 predicts CYP2D6 haplotype functional status with 88% accuracy in a held-out test set and explains 47.5% of the variance in in vitro functional data among star alleles with unknown function. Hubble.2D6 may be a useful tool for assigning function to haplotypes with uncurated function, and used for screening individuals who are at risk of being poor metabolizers.

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“…CYP2D6 activity varies widely among individuals and populations (Gaedigk et al, 2017). A large portion of the observed variability can be explained by known genetic variation within the CYP2D6 gene locus (Gaedigk et al, 2008;Gaedigk et al, 2018a;Ning et al, 2018;Dalton et al, 2019). Searching for additional loci beyond the immediate CYP2D6 gene region, Wang et al (2015) described that rs5758550, located 116 kb downstream of exon 9 of the CYP2D6 gene' is associated with CYP2D6 activity.…”

Section: Introductionmentioning

confidence: 99%

Long-Distance Phasing of a Tentative “Enhancer” Single-Nucleotide Polymorphism With CYP2D6 Star Allele Definitions

et al. 2020

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Background: The CYP2D6 gene locus has been extensively studied over decades, yet a portion of variability in CYP2D6 activity cannot be explained by known sequence variations within the gene, copy number variation, or structural rearrangements. It was proposed that rs5758550, located 116 kb downstream of the CYP2D6 gene locus, increases gene expression and thus contributes to variability in CYP2D6 activity. This finding has, however, not been validated. The purpose of the study was to address a major technological barrier, i.e., experimentally linking rs5758550, also referred to as the "enhancer" single-nucleotide polymorphism (SNP), to CYP2D6 haplotypes >100 kb away. To overcome this challenge is essential to ultimately determine the contribution of the "enhancer" SNP to interindividual variability in CYP2D6 activity. Methods: A large ethnically mixed population sample (n=3,162) was computationally phased to determine linkage between the "enhancer" SNP and CYP2D6 haplotypes (or star alleles). To experimentally validate predicted linkages, DropPhase2D6, a digital droplet PCR (ddPCR)-based method was developed. 10X Genomics Linked-Reads were utilized as a proof of concept. Results: Phasing predicted that the "enhancer" SNP can occur on numerous CYP2D6 haplotypes including CYP2D6*1, *2, *5, and *41 and suggested that linkage is incomplete, i.e., a portion of these alleles do not have the "enhancer" SNP. Phasing also revealed differences among the European and African ancestry data sets regarding the proportion of alleles with and without the "enhancer" SNP. DropPhase2D6 was utilized to confirm or refute the predicted "enhancer" SNP location for individual samples, e.g., of n=3 samples genotyped as *1/*41, rs5758550 was on the *41 allele of two samples and on the *1 allele of one sample. Our findings highlight that the location of the "enhancer" SNP must not be

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

Cited by 44 publications

References 46 publications

Relationship between CYP2D6 genotype, activity score and phenotype in a pediatric Thai population treated with risperidone

Relationship between CYP2D6 genotype, activity score and phenotype in a pediatric Thai population treated with risperidone

Transfer learning enables prediction of CYP2D6 haplotype function

Long-Distance Phasing of a Tentative “Enhancer” Single-Nucleotide Polymorphism With CYP2D6 Star Allele Definitions

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