Publications by authors named "Andrea Gaedigk"

144 Publications

Pharmacogenetics: Chasing Perfection.

Authors:
Andrea Gaedigk

Clin Pharmacol Ther 2019 08;106(2):265-270

Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children's Mercy Kansas City, Kansas City, Missouri, USA.

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http://dx.doi.org/10.1002/cpt.1511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668915PMC
August 2019

Structural variation at the CYP2C locus: Characterization of deletion and duplication alleles.

Hum Mutat 2019 11;40(11):e37-e51

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.

The human CYP2C locus harbors the polymorphic CYP2C18, CYP2C19, CYP2C9, and CYP2C8 genes, and of these, CYP2C19 and CYP2C9 are directly involved in the metabolism of ~15% of all medications. All variant CYP2C19 and CYP2C9 star (*) allele haplotypes currently cataloged by the Pharmacogene Variation (PharmVar) Consortium are defined by sequence variants. To determine if structural variation also occurs at the CYP2C locus, the 10q23.33 region was interrogated across deidentified clinical chromosomal microarray (CMA) data from 20,642 patients tested at two academic medical centers. Fourteen copy number variants that affected the coding region of CYP2C genes were detected in the clinical CMA cohorts, which ranged in size from 39.2 to 1,043.3 kb. Selected deletions and duplications were confirmed by MLPA or ddPCR. Analysis of the clinical CMA and an additional 78,839 cases from the Database of Genomic Variants (DGV) and ClinGen (total n = 99,481) indicated that the carrier frequency of a CYP2C structural variant is ~1 in 1,000, with ~1 in 2,000 being a CYP2C19 full gene or partial-gene deletion carrier, designated by PharmVar as CYP2C19*36 and *37, respectively. Although these structural variants are rare in the general population, their detection will likely improve metabolizer phenotype prediction when interrogated for research and/or clinical testing.
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http://dx.doi.org/10.1002/humu.23855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6810756PMC
November 2019

Ontogeny of Hepatic Sulfotransferases and Prediction of Age-Dependent Fractional Contribution of Sulfation in Acetaminophen Metabolism.

Drug Metab Dispos 2019 08 17;47(8):818-831. Epub 2019 May 17.

Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Mohali, Punjab, India (M.K.L., S.Sh., A.T., S.Si.); Department of Pharmaceutics, University of Washington, Seattle, Washington (D.K.B., B.P.); Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Department of Pediatrics, Children's Mercy Kansas City, Kansas City, Missouri (A.G., R.E.P., J.S.L.); School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri (A.G., R.E.P., J.S.L.); and Simulations Plus, Inc., Lancaster, California (M.B.B.)

Cytosolic sulfotransferases (SULTs), including SULT1A, SULT1B, SULT1E, and SULT2A isoforms, play noteworthy roles in xenobiotic and endobiotic metabolism. We quantified the protein abundances of SULT1A1, SULT1A3, SULT1B1, and SULT2A1 in human liver cytosol samples ( = 194) by liquid chromatography-tandem mass spectrometry proteomics. The data were analyzed for their associations by age, sex, genotype, and ethnicity of the donors. SULT1A1, SULT1B1, and SULT2A1 showed significant age-dependent protein abundance, whereas SULT1A3 was invariable across 0-70 years. The respective mean abundances of SULT1A1, SULT1B1, and SULT2A1 in neonatal samples was 24%, 19%, and 38% of the adult levels. Interestingly, unlike UDP-glucuronosyltransferases and cytochrome P450 enzymes, SULT1A1 and SULT2A1 showed the highest abundance during early childhood (1 to <6 years), which gradually decreased by approx. 40% in adolescents and adults. SULT1A3 and SULT1B1 abundances were significantly lower in African Americans compared with Caucasians. Multiple linear regression analysis further confirmed the association of SULT abundances by age, ethnicity, and genotype. To demonstrate clinical application of the characteristic SULT ontogeny profiles, we developed and validated a proteomics-informed physiologically based pharmacokinetic model of acetaminophen. The latter confirmed the higher fractional contribution of sulfation over glucuronidation in the metabolism of acetaminophen in children. The study thus highlights that the ontogeny-based age-dependent fractional contribution (f) of individual drug-metabolizing enzymes has better potential in prediction of drug-drug interactions and the effect of genetic polymorphisms in the pediatric population.
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http://dx.doi.org/10.1124/dmd.119.086462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614793PMC
August 2019

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2B6 and Efavirenz-Containing Antiretroviral Therapy.

Clin Pharmacol Ther 2019 10 5;106(4):726-733. Epub 2019 Jul 5.

Department of Internal Medicine, Meharry Medical College School of Medicine, Nashville, Tennessee, USA.

The HIV type-1 nonnucleoside reverse transcriptase inhibitor, efavirenz, is widely used to treat HIV type-1 infection. Efavirenz is predominantly metabolized into inactive metabolites by cytochrome P450 (CYP)2B6, and patients with certain CYP2B6 genetic variants may be at increased risk for adverse effects, particularly central nervous system toxicity and treatment discontinuation. We summarize the evidence from the literature and provide therapeutic recommendations for efavirenz prescribing based on CYP2B6 genotypes.
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http://dx.doi.org/10.1002/cpt.1477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739160PMC
October 2019

Clinical Pharmacogenetics Implementation Consortium Guideline for Cytochrome P450 (CYP)2D6 Genotype and Atomoxetine Therapy.

Clin Pharmacol Ther 2019 07 13;106(1):94-102. Epub 2019 Apr 13.

Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Department of Pediatrics, Children's Mercy Kansas City, Kansas City, Missouri, USA.

Atomoxetine is a nonstimulant medication used to treat attention-deficit/hyperactivity disorder (ADHD). Cytochrome P450 (CYP)2D6 polymorphisms influence the metabolism of atomoxetine thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for atomoxetine based on CYP2D6 genotype (updates at www.cpicpgx.org).
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http://dx.doi.org/10.1002/cpt.1409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612570PMC
July 2019

Integrated CYP2D6 interrogation for multiethnic copy number and tandem allele detection.

Pharmacogenomics 2019 01 6;20(1):9-20. Epub 2018 Dec 6.

Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Aim: To comprehensively interrogate CYP2D6 by integrating genotyping, copy number analysis and novel strategies to identify CYP2D6*36 and characterize CYP2D6 duplications.

Methods: Genotyping of 16 CYP2D6 alleles, multiplex ligation-dependent probe amplification (MLPA) and CYP2D6*36 and duplication allele-specific genotyping were performed on 427 African-American, Asian, Caucasian, Hispanic, and Ashkenazi Jewish individuals.

Results: A novel PCR strategy determined that almost half of all CYP2D6*10 (100C>T) alleles are actually *36 (isolated or in tandem with *10) and all identified duplication alleles were characterized. Integrated results from all testing platforms enabled the refinement of genotype frequencies across all studied populations.

Conclusion: The polymorphic CYP2D6 gene requires comprehensive interrogation to characterize allelic variation across ethnicities, which was enabled in this study by integrating multiplexed genotyping, MLPA copy number analysis, novel PCR strategies and duplication allele-specific genotyping.
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http://dx.doi.org/10.2217/pgs-2018-0135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563015PMC
January 2019

Impact of Genetic Variation on Pravastatin Systemic Exposure in Pediatric Hypercholesterolemia.

Clin Pharmacol Ther 2019 06 25;105(6):1501-1512. Epub 2019 Feb 25.

Division of Clinical Pharmacology, Medical Toxicology and Therapeutic Innovation, Children's Mercy, Kansas City, Missouri, USA.

This study investigated the impact of SLCO1B1 genotype on pravastatin systemic exposure in children and adolescents with hypercholesterolemia. Participants (8-20 years) with at least one allelic variant of SLCO1B1 c.521T>C (521TC, n = 15; 521CC, n = 2) and wild-type controls (521TT, n = 15) completed a single oral dose pharmacokinetic study. Interindividual variability of pravastatin acid (PVA) exposure within SLCO1B1 genotype groups exceeded the approximately twofold difference in mean PVA exposure observed between SLCO1B1 genotype groups (P > 0.05, q > 0.10). The 3'α-iso-pravastatin acid and lactone isomer formation in the acidic environment of the stomach prior to absorption also was variable and affected PVA exposure in all genotype groups. The SLCO1B1 c.521 gene variant contributing to variability in systemic exposure to PVA in our pediatric cohort was comparable to previous studies in adults. However, other demographic and physicochemical factors seem to also contribute to interindividual variability in the dose-exposure relationship.
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http://dx.doi.org/10.1002/cpt.1330DOI Listing
June 2019

The Evolution of PharmVar.

Clin Pharmacol Ther 2019 01 7;105(1):29-32. Epub 2018 Dec 7.

School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA.

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http://dx.doi.org/10.1002/cpt.1275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312487PMC
January 2019

CYP2C9*61, a rare missense variant identified in a Puerto Rican patient with low warfarin dose requirements.

Pharmacogenomics 2019 01 6;20(1):3-8. Epub 2018 Dec 6.

Department of Pharmaceutical Sciences, School of Pharmacy, Medical Sciences Campus, University of Puerto Rico, San Juan, PR 00936, Puerto Rico.

Warfarin continues to be the mainstay therapy for preventing thrombus formation. Although pharmacogenetic algorithms have shown higher predictability of the optimal warfarin dose and lower occurrence of bleeding episodes, they often do not include ethno-specific genetic variants relevant to non-Europeans. This case report describes a rare missense variant at exon 9 of CYP2C9 (rs202201137; c.1370A>G transition; p.Asn457Ser) found in a Puerto Rican patient with low warfarin dose requirements (3 mg/day). The haplotype characterized by two amino acid changes, Asn457Ser and Arg144Cys (rs1799853; c.430C>T), has been designated CYP2C9*61 by the Pharmacogene Variation Consortium. According to prediction scores assessed with the Combined Annotation Dependent Depletion tool, CYP2C9*61 (p.Asn457Ser) was classified as nondeleterious, therefore its impact on CYP2C9 enzymatic activity cannot be postulated.
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http://dx.doi.org/10.2217/pgs-2018-0143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479273PMC
January 2019

The Case for Pharmacogenetics-Guided Prescribing of Codeine in Children.

Clin Pharmacol Ther 2019 06 22;105(6):1300-1302. Epub 2018 Nov 22.

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

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http://dx.doi.org/10.1002/cpt.1260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168366PMC
June 2019

CYP2D6 genotype analysis of a Thai population: platform comparison.

Pharmacogenomics 2018 08 11;19(12):947-960. Epub 2018 Jul 11.

Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand.

The highly polymorphic CYP2D6 gene locus leads to a wide range of enzyme activity. Since there are limited data for Thai, the major aim was to investigate CYP2D6 genetic variation in a large Thai population (n = 920). CYP2D6 genotyping was performed using four different platforms. Genotype call rates of the Luminex xTAG and AmpliChip CYP450 test were 96.5% and 87.4%, respectively. Based on Luminex xTAG data, the most common alleles and genotypes were *1 0 (49.6%), *1 (24.6%), *2 (10.8%), *5 (6.7%), *41 (6.5%) and *1/*10 (23.9%), *10/*10 (21.5%), *2/*10 (9.4%), *5/*10 (6.9%), *10/*41 (5.7%), respectively. Challenges and limitations of the platforms evaluated are discussed. These data add to our knowledge regarding interethnic variability in CYP2D6 activity and contribute to improving drug therapy in the Thai.
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http://dx.doi.org/10.2217/pgs-2018-0075DOI Listing
August 2018

PASSPORT-seq: A Novel High-Throughput Bioassay to Functionally Test Polymorphisms in Micro-RNA Target Sites.

Front Genet 2018 15;9:219. Epub 2018 Jun 15.

Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States.

Next-generation sequencing (NGS) studies have identified large numbers of genetic variants that are predicted to alter miRNA-mRNA interactions. We developed a novel high-throughput bioassay, PASSPORT-seq, that can functionally test in parallel 100s of these variants in miRNA binding sites (mirSNPs). The results are highly reproducible across both technical and biological replicates. The utility of the bioassay was demonstrated by testing 100 mirSNPs in HEK293, HepG2, and HeLa cells. The results of several of the variants were validated in all three cell lines using traditional individual luciferase assays. Fifty-five mirSNPs were functional in at least one of three cell lines (FDR ≤ 0.05); 11, 36, and 27 of them were functional in HEK293, HepG2, and HeLa cells, respectively. Only four of the variants were functional in all three cell lines, which demonstrates the cell-type specific effects of mirSNPs and the importance of testing the mirSNPs in multiple cell lines. Using PASSPORT-seq, we functionally tested 111 variants in the 3' UTR of 17 pharmacogenes that are predicted to alter miRNA regulation. Thirty-three of the variants tested were functional in at least one cell line.
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http://dx.doi.org/10.3389/fgene.2018.00219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013768PMC
June 2018

Stargazer: a software tool for calling star alleles from next-generation sequencing data using CYP2D6 as a model.

Genet Med 2019 02 6;21(2):361-372. Epub 2018 Jun 6.

Department of Genome Sciences, School of Medicine, University of Washington, Seattle, Washington, USA.

Purpose: Genotyping CYP2D6 is important for precision drug therapy because the enzyme it encodes metabolizes approximately 25% of drugs, and its activity varies considerably among individuals. Genotype analysis of CYP2D6 is challenging due to its highly polymorphic nature. Over 100 haplotypes (star alleles) have been defined for CYP2D6, some involving a gene conversion with its nearby nonfunctional but highly homologous paralog CYP2D7. We present Stargazer, a new bioinformatics tool that uses next-generation sequencing (NGS) data to call star alleles for CYP2D6 ( https://stargazer.gs.washington.edu/stargazerweb/ ). Stargazer is currently being extended for other pharmacogenes.

Methods: Stargazer identifies star alleles from NGS data by detecting single nucleotide variants, insertion-deletion variants, and structural variants. Stargazer detects structural variation, including gene deletions, duplications, and conversions, by calculating paralog-specific copy numbers from read depths.

Results: We applied Stargazer to the NGS data of 32 ethnically diverse HapMap trios that were genotyped by TaqMan assays, long-range polymerase chain reaction, quantitative multiplex polymerase chain reaction, high-resolution melting analysis, and/or Sanger sequencing. CYP2D6 genotyping by Stargazer was 99.0% concordant with the data obtained by these methods, and showed that 28.1% of the samples had structural variation including CYP2D6/CYP2D7 hybrids.

Conclusion: Accurate genotyping of pharmacogenes with NGS and subsequent allele calling with Stargazer will aid the implementation of precision drug therapy.
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http://dx.doi.org/10.1038/s41436-018-0054-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281872PMC
February 2019

Age- and Genotype-Dependent Variability in the Protein Abundance and Activity of Six Major Uridine Diphosphate-Glucuronosyltransferases in Human Liver.

Clin Pharmacol Ther 2019 01 12;105(1):131-141. Epub 2018 Jul 12.

Department of Pharmaceutics, University of Washington, Seattle, Washington, USA.

The ontogeny of hepatic uridine diphosphate-glucuronosyltransferases (UGTs) was investigated by determining their protein abundance in human liver microsomes isolated from 136 pediatric (0-18 years) and 35 adult (age >18 years) donors using liquid chromatography / tandem mass spectrometry (LC-MS/MS) proteomics. Microsomal protein abundances of UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15 increased by ∼8, 55, 35, 33, 8, and 3-fold from neonates to adults, respectively. The estimated age at which 50% of the adult protein abundance is observed for these UGT isoforms was between 2.6-10.3 years. Measured in vitro activity was generally consistent with the protein data. UGT1A1 protein abundance was associated with multiple single nucleotide polymorphisms exhibiting noticeable ontogeny-genotype interplay. UGT2B15 rs1902023 (*2) was associated with decreased protein activity without any change in protein abundance. Taken together, these data are invaluable to facilitate the prediction of drug disposition in children using physiologically based pharmacokinetic modeling as demonstrated here for zidovudine and morphine.
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http://dx.doi.org/10.1002/cpt.1109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222000PMC
January 2019

Ten Years' Experience with the CYP2D6 Activity Score: A Perspective on Future Investigations to Improve Clinical Predictions for Precision Therapeutics.

J Pers Med 2018 Apr 17;8(2). Epub 2018 Apr 17.

Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy Kansas City, 2401 Gillham Rd, Kanas City, MO 64108, USA.

The seminal paper on the CYP2D6 Activity Score (AS) was first published ten years ago and, since its introduction in 2008, it has been widely accepted in the field of pharmacogenetics. This scoring system facilitates the translation of highly complex diplotype data into a patient’s phenotype to guide drug therapy and is at the core of all gene/drug pair guidelines issued by the Clinical Pharmacogenetics Implementation Consortium (CPIC). The AS, however, only explains a portion of the variability observed among individuals and ethnicities. In this review, we provide an overview of sources in addition to genotype that contribute to the variability in CYP2D6-mediated drug metabolism and discuss other factors, genetic and non-genetic, that likely contribute to the observed variability in CYP2D6 enzymatic activity.
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http://dx.doi.org/10.3390/jpm8020015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023391PMC
April 2018

Polymorphic Expression of UGT1A9 is Associated with Variable Acetaminophen Glucuronidation in Neonates: A Population Pharmacokinetic and Pharmacogenetic Study.

Clin Pharmacokinet 2018 10;57(10):1325-1336

Division of Clinical Pharmacology, Children's National Health System, Washington, DC, USA.

Introduction: Acetaminophen (paracetamol, APAP) is widely used as an analgesic and antipyretic drug in children and neonates. A number of enzymes contribute to the metabolism of acetaminophen, and genetic factors might be important to explain variability in acetaminophen metabolism among individuals.

Methods: The current investigation utilized a previously published parent-metabolite population pharmacokinetic model describing acetaminophen glucuronidation, sulfation, and oxidation to examine the potential role of genetic variability on the relevant metabolic pathways. Neonates were administered 30-min intravenous infusions of acetaminophen 15 mg/kg every 12 h (< 28 weeks' gestational age [GA]) or every 8 h (≥ 28 weeks GA) for 48 h. A total of 18 sequence variations (SVs) in UDP-glucuronosyltransferase (UGT), sulfotransferase (SULT), and cytochrome P450 (CYP) genes from 33 neonates (aged 1-26 days) were examined in a stepwise manner for an effect on the metabolic formation clearance of acetaminophen by glucuronidation (UGT), sulfation (SULT), and oxidation (CYP). The stepwise covariate modeling procedure was performed using NONMEM version 7.3.

Results: Incorporation of genotype as a covariate for one SV located in the UGT1A9 gene promoter region (rs3832043, - 118 > insT, T > T) significantly improved model fit (likelihood ratio test, p < 0.001) and reduced between-subject variability in glucuronide formation clearance. Individuals with the UGT1A9 T polymorphism, indicating insertion of an additional thymidine nucleotide, had a 42% reduction in clearance to APAP-glucuronide as compared to their wild-type counterparts.

Conclusion: This study shows a pharmacogenetic effect of an SV in the UGT1A9 promoter region on the metabolism of acetaminophen in neonates.
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http://dx.doi.org/10.1007/s40262-018-0634-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785200PMC
October 2018

Hepatic Abundance and Activity of Androgen- and Drug-Metabolizing Enzyme UGT2B17 Are Associated with Genotype, Age, and Sex.

Drug Metab Dispos 2018 06 30;46(6):888-896. Epub 2018 Mar 30.

Departments of Pharmaceutics (D.K.B., A.B., H.Z., K.G.C., A.M., B.P.), Genome Sciences (S.L., D.A.N.), Biostatistics (T.A.T.), and Medicine (J.K.A.), University of Washington, Seattle, Washington; Division of Pediatric Pharmacology and Medical Toxicology, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, Missouri (A.G., R.E.P., R.G., J.S.L.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); and Section of Genomic Pediatrics, Department of Pediatrics, and Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin (U.B.)

The major objective of this study was to investigate the association of genetic and nongenetic factors with variability in protein abundance and in vitro activity of the androgen-metabolizing enzyme UGT2B17 in human liver microsomes ( = 455). UGT2B17 abundance was quantified by liquid chromatography-tandem mass spectrometry proteomics, and enzyme activity was determined by using testosterone and dihydrotestosterone as in vitro probe substrates. Genotyping or gene resequencing and mRNA expression were also evaluated. Multivariate analysis was used to test the association of UGT2B17 copy number variation, single nucleotide polymorphisms (SNPs), age, and sex with its mRNA expression, abundance, and activity. UGT2B17 gene copy number and SNPs (rs7436962, rs9996186, rs28374627, and rs4860305) were associated with gene expression, protein levels, and androgen glucuronidation rates in a gene dose-dependent manner. UGT2B17 protein (mean ± S.D. picomoles per milligram of microsomal protein) is sparsely expressed in children younger than 9 years (0.12 ± 0.24 years) but profoundly increases from age 9 years to adults (∼10-fold) with ∼2.6-fold greater abundance in males than in females (1.2 vs. 0.47). Association of androgen glucuronidation with UGT2B15 abundance was observed only in the low UGT2B17 expressers. These data can be used to predict variability in the metabolism of UGT2B17 substrates. Drug companies should include UGT2B17 in early phenotyping assays during drug discovery to avoid late clinical failures.
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http://dx.doi.org/10.1124/dmd.118.080952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938891PMC
June 2018

Impact of SLCO1B1 Genotype on Pediatric Simvastatin Acid Pharmacokinetics.

J Clin Pharmacol 2018 06 22;58(6):823-833. Epub 2018 Feb 22.

Division of Clinical Pharmacology, Medical Toxicology and Therapeutic Innovation, Children's Mercy, Kansas City, MO, USA.

This study investigated the impact of allelic variation in SLCO1B1, a gene encoding for the liver-specific solute carrier organic anion transporter family member 1B1 protein (SLCO1B1), on simvastatin and simvastatin acid (SVA) systemic exposure in children and adolescents. Participants (8-20 years old) with at least 1 variant SLCO1B1 c.521T>C allele (521TC, n = 15; 521CC, n = 2) and 2 wild-type alleles (521TT, n = 15) completed a single oral dose pharmacokinetic study. At equivalent doses, SVA exposure was 6.3- and 2.5-fold greater in 521CC and TC genotypes relative to 521TT (C , 2.1 ± 0.2 vs 1.0 ± 0.5 vs 0.4 ± 0.3 ng/mL; P < .0001; and AUC, 12.1 ± 0.3 vs 4.5 ± 2.5 vs 1.9 ± 1.8 ng·h/mL; P < .0001). The impact of the SLCO1B1 c.521 genotype was more pronounced in children, although considerable interindividual variability in SVA exposure was observed within genotype groups. In addition, SVA systemic exposure was negligible in 25% of pediatric participants. Further investigation of the ontogeny and genetic variation of SVA formation and SLCO1B1-mediated hepatic uptake is necessary to better understand the variability in SVA exposure in children and its clinical consequences.
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http://dx.doi.org/10.1002/jcph.1080DOI Listing
June 2018

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and Tamoxifen Therapy.

Clin Pharmacol Ther 2018 05 31;103(5):770-777. Epub 2018 Jan 31.

Department of Biomedical Data Science, Stanford University, Stanford, California, USA.

Tamoxifen is biotransformed by CYP2D6 to 4-hydroxytamoxifen and 4-hydroxy N-desmethyl tamoxifen (endoxifen), both with greater antiestrogenic potency than the parent drug. Patients with certain CYP2D6 genetic polymorphisms and patients who receive strong CYP2D6 inhibitors exhibit lower endoxifen concentrations and a higher risk of disease recurrence in some studies of tamoxifen adjuvant therapy of early breast cancer. We summarize evidence from the literature and provide therapeutic recommendations for tamoxifen based on CYP2D6 genotype.
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http://dx.doi.org/10.1002/cpt.1007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931215PMC
May 2018

Impact of CYP2D6 on venlafaxine metabolism in Trinidadian patients with major depressive disorder.

Pharmacogenomics 2018 02 12;19(3):197-212. Epub 2018 Jan 12.

Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy Kansas City & Department of Pediatrics, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA.

Aim: This study aimed to assess the impact of CYP2D6 and CYP2C19 variation on venlafaxine (VEN) at steady state in patients from Trinidad and Tobago of Indian and African descent with major depressive disorder.

Patients & Methods: Patients were phenotyped with dextromethorphan, genotyped for CYP2D6 and CYP2C19, and metabolic ratios for VEN obtained at 2-week intervals.

Results: Of 61 patients, 55 were genotyped and phenotyped and 47 completed 8 weeks of VEN treatment. The majority of patients had metabolic ratios for VEN that were consistent with those for dextromethorphan and genotype-predicted phenotype using activity scores. One subject presented with a novel no-function allele, CYP2D6*99. No correlations were observed with CYP2C19 genotype.

Conclusion: CYP2D6 genotype analysis provides valuable information to individualize drug therapy with VEN.
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http://dx.doi.org/10.2217/pgs-2017-0142DOI Listing
February 2018

Precision medicine: does ethnicity information complement genotype-based prescribing decisions?

Ther Adv Drug Saf 2018 Jan 1;9(1):45-62. Epub 2017 Dec 1.

Director, Pharmacogenetics Core Laboratory, Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy-Kansas City, Kansas City, MO and School of Medicine, University of Missouri-Kansas City, MO, USA.

Inter-ethnic differences in drug response are all too well known. These are underpinned by a number of factors, including pharmacogenetic differences across various ethnic populations. Precision medicine relies on genotype-based prescribing decisions with the aim of maximizing efficacy and mitigating the risks. When there is no access to genotyping tests, ethnicity is frequently regarded as a proxy of the patient's probable genotype on the basis of overall population-based frequency of genetic variations in the ethnic group the patient belongs to, with some variations being ethnicity-specific. However, ever-increasing transcontinental migration of populations and the resulting admixing of populations have undermined the utility of self-identified ethnicity in predicting the genetic ancestry, and therefore the genotype, of the patient. An example of the relevance of genetic ancestry of a patient is the inadequate performance of European-derived pharmacogenetic dosing algorithms of warfarin in African Americans, Brazilians and Caribbean Hispanics. Consequently, genotyping a patient potentially requires testing for all known clinically actionable variants that the patient may harbour, and new variants that are likely to be identified using state-of the art next-generation sequencing-based methods. Furthermore, self-identified ethnicity is associated with a number of ethnicity-related attributes and non-genetic factors that potentially influence the risk of phenoconversion (genotype-phenotype discordance), which may adversely impact the success of genotype-based prescribing decisions. Therefore, while genotype-based prescribing decisions are important in implementing precision medicine, ethnicity should not be disregarded.
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http://dx.doi.org/10.1177/2042098617743393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753996PMC
January 2018

The Pharmacogene Variation (PharmVar) Consortium: Incorporation of the Human Cytochrome P450 (CYP) Allele Nomenclature Database.

Clin Pharmacol Ther 2018 03 14;103(3):399-401. Epub 2017 Nov 14.

Department of Genetics, Stanford University, Stanford, California, USA.

The Human Cytochrome P450 (CYP) Allele Nomenclature Database, a critical resource for the pharmacogenetics and genomics communities, has transitioned to the Pharmacogene Variation (PharmVar) Consortium. In this report we provide a summary of the current database, provide an overview of the PharmVar consortium, and highlight the PharmVar database which will serve as the new home for pharmacogene nomenclature.
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http://dx.doi.org/10.1002/cpt.910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836850PMC
March 2018

Variants in the CYP2B6 3'UTR Alter In Vitro and In Vivo CYP2B6 Activity: Potential Role of MicroRNAs.

Clin Pharmacol Ther 2018 07 25;104(1):130-138. Epub 2017 Oct 25.

Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

CYP2B6*6 and CYP2B6*18 are the most clinically important variants causing reduced CYP2B6 protein expression and activity. However, these variants do not account for all variability in CYP2B6 activity. Emerging evidence has shown that genetic variants in the 3'UTR may explain variable drug response by altering microRNA regulation. Five 3'UTR variants were associated with significantly altered efavirenz AUC (8-OH-EFV/EFV) ratios in healthy human volunteers. The rs70950385 (AG>CA) variant, predicted to create a microRNA binding site for miR-1275, was associated with a 33% decreased CYP2B6 activity among normal metabolizers (AG/AG vs. CA/CA (P < 0.05)). In vitro luciferase assays were used to confirm that the CA on the variant allele created a microRNA binding site causing an 11.3% decrease in activity compared to the AG allele when treated with miR-1275 (P = 0.0035). Our results show that a 3'UTR variant contributes to variability in CYP2B6 activity.
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http://dx.doi.org/10.1002/cpt.892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871545PMC
July 2018

Pharmacogenomic Variability of Oral Baclofen Clearance and Clinical Response in Children With Cerebral Palsy.

PM R 2018 03 1;10(3):235-243. Epub 2017 Sep 1.

Division of Rehabilitation Medicine, Children's Mercy-Kansas City, 2401 Gillham Road, Kansas City, MO 64108; Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy, Kansas City, MO.

Background: Pharmacogenomic variability can contribute to differences in pharmacokinetics and clinical responses. Pediatric patients with cerebral palsy with genetic variations have not been studied for these potential differences.

Objective: To determine the genetic sources of variation in oral baclofen clearance and clinical responses.

Design: Pharmacogenomic add-on study to determine variability in oral baclofen clearance and clinical responses.

Setting: Multicenter study based in academic pediatric cerebral palsy clinics.

Participants: A total of 49 patients with cerebral palsy who had participated in an oral baclofen pharmacokinetic/pharmacodynamic study.

Methods Or Interventions: Of 53 participants in a pharmacokinetic/pharmacodynamic trial, 49 underwent genetic analysis of 307 key genes and 4535 single-nucleotide polymorphisms involved in drug absorption, distribution, metabolism, and excretion. Associations between genotypes and phenotypes of baclofen disposition (weight-corrected and allometrically scaled clearance) and clinical endpoints (improvement from baseline in mean hamstring Modified Tardieu Scale scores from baseline for improvement of R1 spastic catch) were determined by univariate analysis with correction for multiple testing by false discovery rate.

Main Outcome Measurements: Primary outcome measures were the genotypic and phenotypic variability of oral baclofen in allometrically scaled clearance and change in the Modified Tardieu Scale angle compared to baseline.

Results: After univariate analysis of the data, the SNP of ABCC9 (rs11046232, heterozygous AT versus the reference TT genotype) was associated with a 2-fold increase in oral baclofen clearance (mean 0.51 ± standard deviation 0.05 L/h/kg for the AT genotype versus 0.25 ± 0.07 L/h/kg for the TT genotype, adjusted P < .001). Clinical responses were associated with decreased spasticity by Modified Tardieu Scale in allelic variants with SNPs ABCC12, SLC28A1, and PPARD.

Conclusions: Genetic variation in ABCC9 affecting oral baclofen clearance highlights the need for continued studies of genetic polymorphisms to better characterize variable drug response in children with cerebral palsy. Single-nucleotide polymorphisms in ABCC12, SLC28A1, and PPARD were associated with varied responses, which warrants further investigation to determine their effect on spasticity.

Level Of Evidence: II.
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http://dx.doi.org/10.1016/j.pmrj.2017.08.441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880219PMC
March 2018

Genetic and Nongenetic Factors Associated with Protein Abundance of Flavin-Containing Monooxygenase 3 in Human Liver.

J Pharmacol Exp Ther 2017 11 17;363(2):265-274. Epub 2017 Aug 17.

Departments of Pharmaceutics (M.X., D.K.B., K.G.C., K.E.T., B.P.), Medicinal Chemistry (C.K.Y., A.E.R.), and Genome Sciences (D.N.), University of Washington, Seattle, Washington; Department of Clinical Pharmacology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China (M.X.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.S.); Division of Pediatric Pharmacology and Medical Toxicology, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, Missouri (A.G., R.E.P., R.G., J.S.L.); and Section of Genomic Pediatrics, Department of Pediatrics, and Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin (U.B.)

Hepatic flavin-containing mono-oxygenase 3 (FMO3) metabolizes a broad array of nucleophilic heteroatom (e.g., or )-containing xenobiotics (e.g., amphetamine, sulindac, benzydamine, ranitidine, tamoxifen, nicotine, and ethionamide), as well as endogenous compounds (e.g., catecholamine and trimethylamine). To predict the effect of genetic and nongenetic factors on the hepatic metabolism of FMO3 substrates, we quantified FMO3 protein abundance in human liver microsomes (HLMs; = 445) by liquid chromatography-tandem mass chromatography proteomics. Genotyping/gene resequencing, mRNA expression, and functional activity (with benzydamine as probe substrate) of FMO3 were also evaluated. FMO3 abundance increased 2.2-fold (13.0 ± 11.4 pmol/mg protein vs. 28.0 ± 11.8 pmol/mg protein) from neonates to adults. After 6 years of age, no significant difference in FMO3 abundance was found between children and adults. Female donors exhibited modestly higher mRNA fragments per kilobase per million reads values (139.9 ± 76.9 vs. 105.1 ± 73.1; < 0.001) and protein FMO3 abundance (26.7 ± 12.0 pmol/mg protein vs. 24.1 ± 12.1 pmol/mg protein; < 0.05) compared with males. Six single nucleotide polymorphisms (SNPs), including rs2064074, rs28363536, rs2266782 (E158K), rs909530 (N285N), rs2266780 (E308G), and rs909531, were associated with significantly decreased protein abundance. FMO3 abundance in individuals homozygous and heterozygous for haplotype 3 (H3), representing variant alleles for all these SNPs (except rs2066534), were 50.8% ( < 0.001) and 79.5% ( < 0.01), respectively, of those with the reference homozygous haplotype (H1, representing wild-type). In summary, FMO3 protein abundance is significantly associated with age, gender, and genotype. These data are important in predicting FMO3-mediated heteroatom-oxidation of xenobiotics and endogenous biomolecules in the human liver.
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http://dx.doi.org/10.1124/jpet.117.243113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697103PMC
November 2017

Association between Genotypes and the Risk of Antidepressant Discontinuation, Dosage Modification and the Occurrence of Maternal Depression during Pregnancy.

Front Pharmacol 2017 17;8:402. Epub 2017 Jul 17.

Research Center, CHU Sainte-JustineMontreal, QC, Canada.

Polymorphic expression of drug metabolizing enzymes affects the metabolism of antidepressants, and thus can contribute to drug response and/or adverse events. Pregnancy itself can affect CYP2D6 activity with profound variations determined by genotype. To investigate the association between genotype and the risk of antidepressant discontinuation, dosage modification, and the occurrence of maternal , Antidepressants, Depression during pregnancy. Data from the Organization of Teratology Information Specialists (OTIS) Antidepressants in Pregnancy Cohort, 2006-2010, were used. Women were eligible if they were within 14 completed weeks of pregnancy at recruitment and exposed to an antidepressant or having any exposures considered non-teratogenic. Gestational antidepressant usage was self-reported and defined as continuous/discontinued use, and non-use; dosage modification was further documented. Maternal depression and anxiety were measured every trimester using the telephone interviewer-administered Edinburgh Postnatal Depression Scale and the Beck Anxiety Inventory, respectively. Saliva samples were collected and used for genotype analyses. Logistic regression models were used to calculate crude and adjusted odds ratios (OR) with 95% confidence intervals. A total of 246 pregnant women were included in the study. The majority were normal metabolizers (NM, = 204, 83%); 3.3% ( = 8) were ultrarapid metabolizers (UM), 5.7% ( = 14) poor metabolizers (PM), and 8.1% ( = 20) intermediate metabolizers (IM). Among study subjects, 139 women were treated with antidepressants at the beginning of pregnancy, and 21 antidepressant users (15%) discontinued therapy during pregnancy. Adjusting for depressive symptoms, and other potential confounders, the risk of discontinuing antidepressants during pregnancy was nearly four times higher in slow metabolizers (poor or intermediate metabolizers) compared to those with a faster metabolism rate (normal or ultrarapid metabolizers), aOR = 3.57 (95% CI: 1.15-11.11). Predicted CYP2D6 metabolizer status did not impact dosage modifications. Compared with slow metabolizers, significantly higher proportion of women in the fast metabolizer group had depressive symptom in the first trimester (19.81 vs. 5.88%, = 0.049). Almost 21% of treated women remained depressed during pregnancy (14.4% NM-UM; 6.1% PM-IM). Prior knowledge of genotype may help to identify pregnant women at greater risk of antidepressant discontinuation. Twenty percent of women exposed to antidepressants during pregnancy remained depressed, indicating an urgent need for personalized treatment of depression during pregnancy.
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http://dx.doi.org/10.3389/fphar.2017.00402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511844PMC
July 2017

Warfarin Anticoagulation Therapy in Caribbean Hispanics of Puerto Rico: A Candidate Gene Association Study.

Front Pharmacol 2017 7;8:347. Epub 2017 Jun 7.

Department of Pharmaceutical Sciences, School of Pharmacy, University of Puerto RicoSan Juan, PR, United States.

Existing algorithms account for ~50% of observed variance in warfarin dose requirements after including common polymorphisms. However, they do not perform as well in populations other than Caucasians, in part because some ethno-specific genetic variants are overlooked. The objective of the present study was to identify genetic polymorphisms that can explain variability in warfarin dose requirements among Caribbean Hispanics of Puerto Rico. Next-Generation Sequencing of candidate genes and and genotyping by DMET® Plus Assay of cardiovascular patients were performed. We also aimed at characterizing the genomic structure and admixture pattern of this study cohort. Our study used the Extreme Discordant Phenotype approach to perform a case-control association analysis. The variant rs2860905, which was found in all the major haplotypes occurring in the Puerto Rican population, showed stronger association with warfarin sensitivity (<4 mg/day) than common variants and . Although, and are separately contained within two of the haplotypes, 10 subjects with the sensitive phenotype were carriers of only the rs2860905 variant. Other polymorphisms in and were found to be associated with warfarin resistance. Incorporation of rs in a regression model ( = 0.63, MSE = 0.37) that also includes additional genetics (i.e., -1639 G>A; rs1856908; c.IVS9-44A>G/ rs10276036; c.269-965A>G/ rs4783745) and non-genetic factors (i.e., hypertension, diabetes and age) showed better prediction of warfarin dose requirements than and combined (partial = 0.132 vs. 0.023 and 0.007, respectively, < 0.001). The genetic background of Puerto Ricans in the study cohort showed a tri-hybrid admixture pattern, with a slightly higher than expected contribution of Native American ancestry (25%). The genomic diversity of Puerto Ricans is highlighted by the presence of four different major haplotype blocks in the locus. Although, our findings need further replication, this study contributes to the field by identifying novel genetic variants that increase predictability of stable warfarin dosing among Caribbean Hispanics.
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http://dx.doi.org/10.3389/fphar.2017.00347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461284PMC
June 2017

Age-dependent Protein Abundance of Cytosolic Alcohol and Aldehyde Dehydrogenases in Human Liver.

Drug Metab Dispos 2017 09 12;45(9):1044-1048. Epub 2017 Jun 12.

Department of Pharmaceutics, University of Washington, Seattle, Washington (D.K.B., B.P.); Department of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy-Kansas City, Missouri and School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri (A.G., R.E.P., J.S.L.)

Hepatic cytosolic alcohol and aldehyde dehydrogenases (ADHs and ALDHs) catalyze the biotransformation of xenobiotics (e.g., cyclophosphamide and ethanol) and vitamin A. Because age-dependent hepatic abundance of these proteins is unknown, we quantified protein expression of ADHs and ALDH1A1 in a large cohort of pediatric and adult human livers by liquid chromatography coupled with tandem mass spectrometry proteomics. Purified proteins were used as calibrators. Two to three surrogate peptides per protein were quantified in trypsin digests of liver cytosolic samples and calibrator proteins under optimal conditions of reproducibility. Neonatal levels of ADH1A, ADH1B, ADH1C, and ALDH1A1 were 3-, 8-, 146-, and 3-fold lower than the adult levels, respectively. For all proteins, the abundance steeply increased during the first year of life, which mostly reached adult levels during early childhood (age between 1 and 6 years). Only for ADH1A protein abundance in adults (age > 18 year) was ∼40% lower relative to the early childhood group. Abundances of ADHs and ALDH1A1 were not associated with sex in samples with age > 1 year compared with males. Known single nucleotide polymorphisms had no effect on the protein levels of these proteins. Quantification of ADHs and ALDH1A1 protein levels could be useful in predicting disposition and response of substrates of these enzymes in younger children.
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http://dx.doi.org/10.1124/dmd.117.076463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5563927PMC
September 2017