Erratum: Constellation: a tool for rapid, automated phenotype assignment of a highly polymorphic pharmacogene, CYP2D6, from whole-genome sequences

Twist, Greyson P; Gaedigk, Andrea; Miller, Neil; Farrow, Emily; Willig, Laurel K.; Dinwiddie, Darrell L.; Petrikin, Josh E; Soden, Sarah E; Herd, Suzanne; Gibson, Margaret Dunlop; Cakici, Julie A.; Riffel, Amanda K.; Leeder, J. Steven; Dinakarpandian, Deendayal

doi:10.1038/npjgenmed.2016.39

Cited by 13 publications

(9 citation statements)

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“…CYP2C9 and UGT1A3 genotype calls were made as following: CYP2C9 genotype was called using Astrolabe, a bioinformatic tool that allows star allele calling from NGS data. 33,34 Astrolabe has been expanded to CYP2C9 and 2C19 (manuscript in preparation). For UGT1A3, an SNP report was generated and star alleles manually called using definitions per the UGT Nomenclature site at https://www.pharm acoge nomics.pha.ulaval.ca/ugt-allel es-nomen clatu re/.…”

Section: Subjectsmentioning

confidence: 99%

Impact of SLCO1B1 Genetic Variation on Rosuvastatin Systemic Exposure in Pediatric Hypercholesterolemia

Wagner

Abdel‐Rahman

Gaedigk

et al. 2020

Clinical Translational Sci

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This study investigated the impact of SLCO1B1 genotype on rosuvastatin systemic exposure in hypercholesterolemic children and adolescents. Participants (8-21 years) with at least one allelic variant of SLCO1B1 c.521T>C (521TC, n = 13; 521CC, n = 2) and wild type controls (521TT, n = 13) completed a single oral dose pharmacokinetic study. The variability contributed by SLCO1B1 c.521 sequence variation to rosuvastatin (RVA) systemic exposure among our pediatric cohort was comparable to previous studies in adults. RVA concentration-time curve from 0-24 hours (AUC 0-24) was 1.4-fold and 2.2-fold higher in participants with c.521TC and c.521CC genotype compared 521TT participants, respectively. Interindividual variability of RVA exposure within SLCO1B1 genotype groups exceeded the ~ 1.5-fold to 2-fold difference in mean RVA exposure observed among SLCO1B1 genotype groups, suggesting that other factors also contribute to interindividual variability in the rosuvastatin dose-exposure relationship. A multivariate model performed confirmed SLCO1B1 c.521T>C genotype as the primary factor contributing to RVA systemic exposure in this pediatric cohort, accounting for ~ 30% of the variability RVA AUC 0-24. However, of the statins investigated to date in the pediatric population, RVA has the lowest magnitude of variability in systemic exposure. Rosuvastatin (RVA) is a hydrophilic, synthetic inhibitor of 3-hydroxy-3-methyl-glutaryl Coenzyme A reductase, labeled to treat children 8 years and older with heterozygous familial hypercholesterolemia. 1-3 RVA is administered in active acid form and undergoes hepatocellular uptake via the drug transporters, OATP1B1, OATP1B3, OATP2B1, and NTCP. 1,4 Minor cytochrome P450 (CYP)-mediated metabolism via CYP2C9 leads to the formation of a minimally active metabolite, N-desmethyl rosuvastatin (NDMRV; Figure 1). 1,2 RVA undergoes phase II metabolism via UGT1A3 leading to the formation of an inactive metabolite, rosuvastatin lactone (RVL). 5 RVA is also a substrate for BCRP, responsible for hepatic clearance into the bile. 6,7 Due to its hydrophilic nature, RVA, similar to pravastatin, may experience less passive diffusion across the blood brain barrier 8,9 and skeletal muscle, 1,10-15 making it a potentially safer statin alternative for maturing brains and myocytes in children compared with highly lipophilic statin agents (e.g., simvastatin). Two double-blind, randomized, placebo-controlled trials of rosuvastatin in children (ages 6-17 years) have demonstrated

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Section: Subjectsmentioning

confidence: 99%

Impact of SLCO1B1 Genetic Variation on Rosuvastatin Systemic Exposure in Pediatric Hypercholesterolemia

Wagner

Abdel‐Rahman

Gaedigk

et al. 2020

Clinical Translational Sci

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“…Aldy is a computational tool that performs allelic decomposition of highly polymorphic, multi-copy genes through the use of the whole or targeted genome sequencing data and identifies multiple rare and novel alleles for several important pharmacogenes Numanagić et al (2018) Astrolabe Astrolabe (former Constellation) is a computational method and probabilistic scoring system that enables automated ascertainment of CYP2D6 and CYP2D19 activity scores from the unphased NGS data, aligned with the catalog of pharmacogenetic alleles with high percentage of analytic sensitivity and specificity Twist et al (2017) Cypripi…”

Section: Aldymentioning

confidence: 99%

Applying Next-Generation Sequencing Platforms for Pharmacogenomic Testing in Clinical Practice

et al. 2021

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Pharmacogenomics (PGx) studies the use of genetic data to optimize drug therapy. Numerous clinical centers have commenced implementing pharmacogenetic tests in clinical routines. Next-generation sequencing (NGS) technologies are emerging as a more comprehensive and time- and cost-effective approach in PGx. This review presents the main considerations for applying NGS in guiding drug treatment in clinical practice. It discusses both the advantages and the challenges of implementing NGS-based tests in PGx. Moreover, the limitations of each NGS platform are revealed, and the solutions for setting up and management of these technologies in clinical practice are addressed.

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“…21,29 In addition, bioinformatic tools have been developed to computationally infer CYP2D6 star (*) allele diplotypes from NGS-derived variant call files and binary alignment map files. [30][31][32][33][34][35][36]…”

Section: Clinical Testingmentioning

confidence: 99%

Recommendations for Clinical CYP2D6 Genotyping Allele Selection

Pratt

Cavallari

Tredici

et al. 2021

The Journal of Molecular Diagnostics

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Erratum: Constellation: a tool for rapid, automated phenotype assignment of a highly polymorphic pharmacogene, CYP2D6, from whole-genome sequences

Cited by 13 publications

References 0 publications

Impact of SLCO1B1 Genetic Variation on Rosuvastatin Systemic Exposure in Pediatric Hypercholesterolemia

Impact of SLCO1B1 Genetic Variation on Rosuvastatin Systemic Exposure in Pediatric Hypercholesterolemia

Applying Next-Generation Sequencing Platforms for Pharmacogenomic Testing in Clinical Practice

Recommendations for Clinical CYP2D6 Genotyping Allele Selection

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