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Clinical Pharmacogenetics Implementation Consortium

Marco Alessandrini, Mamoonah Chaudhry, Tyren M Dodgen, Michael S Pepper
In a move indicative of the enthusiastic support of precision medicine, the U.S. President Barack Obama announced the Precision Medicine Initiative in January 2015. The global precision medicine ecosystem is, thus, receiving generous support from the United States ($215 million), and numerous other governments have followed suit. In the context of precision medicine, drug treatment and prediction of its outcomes have been important for nearly six decades in the field of pharmacogenomics. The field offers an elegant solution for minimizing the effects and occurrence of adverse drug reactions (ADRs)...
October 2016: Omics: a Journal of Integrative Biology
Ingolf Cascorbi, Anneke Nina Werk
INTRODUCTION: Cancer pharmacogenetics usually considers tumor-specific targets. However, hereditary genetic variants may interfere with the pharmacokinetics of antimetabolites and other anti-cancer drugs, which may lead to severe adverse events. AREAS COVERED: Here, the impact of hereditary genes considered in drug labels such as thiopurine S-methyltransferase (TPMT), UDP-glucuronosyltransferase 1A1 (UTG1A1) and dihydropyrimidine dehydrogenase (DPYD) are discussed with respect to guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC)...
September 16, 2016: Expert Opinion on Drug Metabolism & Toxicology
David Ng, Celine S Hong, Larry N Singh, Jennifer J Johnston, James C Mullikin, Leslie G Biesecker
PURPOSE: The aim of the study was to assess exome data for preemptive pharmacogenetic screening for 203 clinically relevant pharmacogenetic variant positions from the Pharmacogenomics Knowledgebase and Clinical Pharmacogenetics Implementation Consortium and identify copy-number variants (CNVs) in CYP2D6. METHODS: We examined the coverage and genotype quality of 203 pharmacogenetic variant positions in 973 exomes compared with five genomes and with five genotyping chip data sets...
August 18, 2016: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Kelly E Caudle, Henry M Dunnenberger, Robert R Freimuth, Josh F Peterson, Jonathan D Burlison, Michelle Whirl-Carrillo, Stuart A Scott, Heidi L Rehm, Marc S Williams, Teri E Klein, Mary V Relling, James M Hoffman
INTRODUCTION: Reporting and sharing pharmacogenetic test results across clinical laboratories and electronic health records is a crucial step toward the implementation of clinical pharmacogenetics, but allele function and phenotype terms are not standardized. Our goal was to develop terms that can be broadly applied to characterize pharmacogenetic allele function and inferred phenotypes. MATERIALS AND METHODS: Terms currently used by genetic testing laboratories and in the literature were identified...
July 21, 2016: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Andrea Gaedigk, Katrin Sangkuhl, Michelle Whirl-Carrillo, Teri Klein, J Steven Leeder
PURPOSE: Owing to its highly polymorphic nature and major contribution to the metabolism and bioactivation of numerous clinically used drugs, CYP2D6 is one of the most extensively studied drug-metabolizing enzymes and pharmacogenes. CYP2D6 alleles confer no, decreased, normal, or increased activity and cause a wide range of activity among individuals and between populations. However, there is no standard approach to translate diplotypes into predicted phenotype. METHODS: We exploited CYP2D6 allele-frequency data that have been compiled for Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines (>60,000 subjects, 173 reports) in order to estimate genotype-predicted phenotype status across major world populations based on activity score (AS) assignments...
July 7, 2016: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Benjamin French, Le Wang, Brian F Gage, Richard B Horenstein, Nita A Limdi, Stephen E Kimmel
OBJECTIVE: Randomized trials have reported inconsistent evidence on the effectiveness of algorithms that use genotypes to initiate warfarin therapy. The Clarification of Optimal Anticoagulation through Genetics (COAG) trial initiated therapy on the basis of predicted maintenance doses, with a pharmacogenetic-guided algorithm in one study group and a clinically guided algorithm in the other. The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) consortium initiated therapy on the basis of loading doses, with an algorithm-based prediction in one study group and a fixed-dose regimen in the other...
October 2016: Pharmacogenetics and Genomics
J Kevin Hicks, David Stowe, Marc A Willner, Maya Wai, Thomas Daly, Steven M Gordon, Bret A Lashner, Sumit Parikh, Robert White, Kathryn Teng, Timothy Moss, Angelika Erwin, Jeffrey Chalmers, Charis Eng, Scott Knoer
The number of clinically relevant gene-based guidelines and recommendations pertaining to drug prescribing continues to grow. Incorporating gene-drug interaction information into the drug-prescribing process can help optimize pharmacotherapy outcomes and improve patient safety. However, pharmacogenomic implementation barriers exist such as integration of pharmacogenomic results into electronic health records (EHRs), development and deployment of pharmacogenomic decision support tools to EHRs, and feasible models for establishing ambulatory pharmacogenomic clinics...
August 2016: Pharmacotherapy
W Yang, G Wu, U Broeckel, C A Smith, V Turner, C E Haidar, S Wang, R Carter, S E Karol, G Neale, K R Crews, J J Yang, C G Mullighan, J R Downing, W E Evans, M V Relling
We compared whole exome sequencing (WES, n = 176 patients) and whole genome sequencing (WGS, n = 68) and clinical genotyping (DMET array-based approach) for interrogating 13 genes with Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. We focused on 127 CPIC important variants: 103 single nucleotide variations (SNV), 21 insertion/deletions (Indel), HLA-B alleles, and two CYP2D6 structural variations. WES and WGS provided interrogation of nonoverlapping sets of 115 SNV/Indels with call rate >98%...
October 2016: Clinical Pharmacology and Therapeutics
James M Hoffman, Henry M Dunnenberger, J Kevin Hicks, Kelly E Caudle, Michelle Whirl Carrillo, Robert R Freimuth, Marc S Williams, Teri E Klein, Josh F Peterson
To move beyond a select few genes/drugs, the successful adoption of pharmacogenomics into routine clinical care requires a curated and machine-readable database of pharmacogenomic knowledge suitable for use in an electronic health record (EHR) with clinical decision support (CDS). Recognizing that EHR vendors do not yet provide a standard set of CDS functions for pharmacogenetics, the Clinical Pharmacogenetics Implementation Consortium (CPIC) Informatics Working Group is developing and systematically incorporating a set of EHR-agnostic implementation resources into all CPIC guidelines...
July 2016: Journal of the American Medical Informatics Association: JAMIA
W S Bush, D R Crosslin, A Owusu-Obeng, J Wallace, B Almoguera, M A Basford, S J Bielinski, D S Carrell, J J Connolly, D Crawford, K F Doheny, C J Gallego, A S Gordon, B Keating, J Kirby, T Kitchner, S Manzi, A R Mejia, V Pan, C L Perry, J F Peterson, C A Prows, J Ralston, S A Scott, A Scrol, M Smith, S C Stallings, T Veldhuizen, W Wolf, S Volpi, K Wiley, R Li, T Manolio, E Bottinger, M H Brilliant, D Carey, R L Chisholm, C G Chute, J L Haines, H Hakonarson, J B Harley, I A Holm, I J Kullo, G P Jarvik, E B Larson, C A McCarty, M S Williams, J C Denny, L J Rasmussen-Torvik, D M Roden, M D Ritchie
Genetic variation can affect drug response in multiple ways, although it remains unclear how rare genetic variants affect drug response. The electronic Medical Records and Genomics (eMERGE) Network, collaborating with the Pharmacogenomics Research Network, began eMERGE-PGx, a targeted sequencing study to assess genetic variation in 82 pharmacogenes critical for implementation of "precision medicine." The February 2015 eMERGE-PGx data release includes sequence-derived data from ∼5,000 clinical subjects. We present the variant frequency spectrum categorized by variant type, ancestry, and predicted function...
August 2016: Clinical Pharmacology and Therapeutics
J C Stingl, K S Just, K Kaumanns, M Schurig-Urbaniak, C Scholl, D von Mallek, J Brockmöller
BACKGROUND: Pharmacogenetics are an important component in the individualization of treatment; however, pharmacogenetic diagnostics have so far not been used to any great extent in clinical practice. A consistent consideration of individual patient factors, such as pharmacogenetics may help to improve drug therapy and increase individual safety and efficacy aspects. OBJECTIVE: A brief summary of structures and effects of genetic variations on drug efficacy is presented...
March 2016: Der Internist
R S Gammal, M H Court, C E Haidar, O F Iwuchukwu, A H Gaur, M Alvarellos, C Guillemette, J L Lennox, M Whirl-Carrillo, S S Brummel, M J Ratain, T E Klein, B R Schackman, K E Caudle, D W Haas
The antiretroviral protease inhibitor atazanavir inhibits hepatic uridine diphosphate glucuronosyltransferase (UGT) 1A1, thereby preventing the glucuronidation and elimination of bilirubin. Resultant indirect hyperbilirubinemia with jaundice can cause premature discontinuation of atazanavir. Risk for bilirubin-related discontinuation is highest among individuals who carry two UGT1A1 decreased function alleles (UGT1A1*28 or *37). We summarize published literature that supports this association and provide recommendations for atazanavir prescribing when UGT1A1 genotype is known (updates at www...
April 2016: Clinical Pharmacology and Therapeutics
David R Crosslin, Peggy D Robertson, David S Carrell, Adam S Gordon, David S Hanna, Amber Burt, Stephanie M Fullerton, Aaron Scrol, James Ralston, Kathleen Leppig, Andrea Hartzler, Eric Baldwin, Mariza de Andrade, Iftikhar J Kullo, Gerard Tromp, Kimberly F Doheny, Marylyn D Ritchie, Paul K Crane, Deborah A Nickerson, Eric B Larson, Gail P Jarvik
BACKGROUND: In an effort to return actionable results from variant data to electronic health records (EHRs), participants in the Electronic Medical Records and Genomics (eMERGE) Network are being sequenced with the targeted Pharmacogenomics Research Network sequence platform (PGRNseq). This cost-effective, highly-scalable, and highly-accurate platform was created to explore rare variation in 84 key pharmacogenetic genes with strong drug phenotype associations. METHODS: To return Clinical Laboratory Improvement Amendments (CLIA) results to our participants at the Group Health Cooperative, we sequenced the DNA of 900 participants (61 % female) with non-CLIA biobanked samples...
2015: Genome Medicine
Y Saito, L K Stamp, K E Caudle, M S Hershfield, E M McDonagh, J T Callaghan, W Tassaneeyakul, T Mushiroda, N Kamatani, B R Goldspiel, E J Phillips, T E Klein, M T M Lee
The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for HLA-B*58:01 Genotype and Allopurinol Dosing was originally published in February 2013. We reviewed the recent literature and concluded that none of the evidence would change the therapeutic recommendations in the original guideline; therefore, the original publication remains clinically current. However, we have updated the Supplemental Material and included additional resources for applying CPIC guidelines into the electronic health record...
January 2016: Clinical Pharmacology and Therapeutics
J K Hicks, J R Bishop, K Sangkuhl, D J Müller, Y Ji, S G Leckband, J S Leeder, R L Graham, D L Chiulli, A LLerena, T C Skaar, S A Scott, J C Stingl, T E Klein, K E Caudle, A Gaedigk
Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs, thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at
August 2015: Clinical Pharmacology and Therapeutics
David R Bright, Diane M Calinski, David F Kisor
OBJECTIVE: To outline how the inclusion of pharmacogenetic data lends additional information in the overall decision making relative to drug therapy in the elderly patient. DATA SOURCES: The National Center for Biotechnology's PubMed database was searched for relevant pharmacogenetic-based dosing guidelines, as well as papers discussing drug use, and pharmacogenetics in the elderly. Google Scholar was also searched for the related documents. STUDY SELECTION: Papers cited were those that presented a rationale for drug therapy in the elderly, presented pharmacogenetic-based dosing guidelines with supporting information, and specifically discussed pharmacogenetics and other therapeutic principles relative to drug therapy in the elderly...
April 2015: Consultant Pharmacist: the Journal of the American Society of Consultant Pharmacists
Payman Shahabi, Marie-Pierre Dubé
Pharmacogenomics (PGx) is the science that examines how an individual's genetic make-up affects the safety and efficacy of therapeutic drugs. PGx of response to cardiovascular (CV) medications is of the most successfully translated branches of PGx into the clinical workout. However, the clinical implementation of PGx of CV drugs is yet far beyond the growth of our understanding of the role of genetics in drug therapy. A considerable amount of efforts have been devoted by the regulatory agents like the food and drug administration (FDA) as well as the expert-based networks such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) to overcome the existing barriers...
April 1, 2015: International Journal of Cardiology
K A Birdwell, B Decker, J M Barbarino, J F Peterson, C M Stein, W Sadee, D Wang, A A Vinks, Y He, J J Swen, J S Leeder, Rhn van Schaik, K E Thummel, T E Klein, K E Caudle, I A M MacPhee
Tacrolimus is the mainstay immunosuppressant drug used after solid organ and hematopoietic stem cell transplantation. Individuals who express CYP3A5 (extensive and intermediate metabolizers) generally have decreased dose-adjusted trough concentrations of tacrolimus as compared with those who are CYP3A5 nonexpressers (poor metabolizers), possibly delaying achievement of target blood concentrations. We summarize evidence from the published literature supporting this association and provide dosing recommendations for tacrolimus based on CYP3A5 genotype when known (updates at www...
July 2015: Clinical Pharmacology and Therapeutics
Wayne T Nicholson, Christine M Formea
No abstract text is available yet for this article.
February 2015: Clinical Chemistry
K E Caudle, A E Rettie, M Whirl-Carrillo, L H Smith, S Mintzer, M T M Lee, T E Klein, J T Callaghan
Phenytoin is a widely used antiepileptic drug with a narrow therapeutic index and large interpatient variability, partly due to genetic variations in the gene encoding cytochrome P450 (CYP)2C9 (CYP2C9). Furthermore, the variant allele HLA-B*15:02, encoding human leukocyte antigen, is associated with an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide recommendations for the use of phenytoin based on CYP2C9 and/or HLA-B genotype (also available on PharmGKB: http://www...
November 2014: Clinical Pharmacology and Therapeutics
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