Sunday, July 23, 2017

The Roles of CYP2C19 and CYP3A4 in Voriconazole Pharmacogenetics

Voriconazole is a triazole antifungal agent used to treat serious fungal infections. It is primarily used in immunocompromised patients, such as those undergoing organ transplantation. CYP2C19 is the primary enzyme responsible for voriconazole metabolism. CYP3A4, CYP3A5 and CYP2C9 also play a role, secondary to CYP2C19. The influence of genetic polymorphisms in CYP2C19 is well documented in clinical studies, and the Clinical Pharmacogenetics Implementation Consortium (CPIC) recently released guideline for voriconazole dosing based on CYP2C19 genotype.

In the August issue of Clinical Pharmacology and Therapeutics, Gautier-Veyret et al wrote a perspective piece discussing two retrospective studies showing that genetic variations in CYP3A4 gene may influence voriconazole trough concentrations, suggesting that in addition to CYP2C19, CYP3A4 should also be genotyped for voriconazole dosing.

In response to this, CPIC guideline authors Walsh et al acknowledged the different opinions on the role of CYP3A4 in voriconazole pharmacokinetics and clarified the reasons why CPIC authors feel there is NOT sufficient evidence to recommend altered voriconazole dosing based on genetic polymorphisms in CYP3A4/CYP3A5.

For further details see both articles in the August edition of Clinical Pharmacology and Therapeutics:

Walsh TJ, Moriyama B, Penzak SR, Klein TE, Caudle KE.
Clin Pharmacol Ther. 2017 Aug;102(2):190. doi: 10.1002/cpt.681. Epub 2017 Apr 29. 
PMID: 28455946

Gautier-Veyret E, Fonrose X, Stanke-Labesque F.
Clin Pharmacol Ther. 2017 Aug;102(2):189. doi: 10.1002/cpt.662. Epub 2017 May 26. 

Friday, July 7, 2017

Curators' Favorite Papers

The Impact of Whole-Genome Sequencing on the Primary Care and Outcomes of Healthy Adult Patients: A Pilot Randomized Trial

Jason L. Vassy, MD, MPH, SM; Kurt D. Christensen, PhD, MPH; Erica F. Schonman, MPH; Carrie L. Blout, MS, CGC; Jill O. Robinson, MA; Joel B. Krier, MD; Pamela M. Diamond, PhD; Matthew Lebo, PhD; Kalotina Machini, PhD; Danielle R. Azzariti, MS, CGC; Dmitry Dukhovny, MD, MPH; David W. Bates, MD, MSc; Calum A. MacRae, MD, PhD; Michael F. Murray, MD; Heidi L. Rehm, PhD; Amy L. McGuire, JD, PhD; and Robert C. Green, MD, MPH for the MedSeq Project

This study, published  in the Annals of Internal Medicine, received a lot of attention in prominent media outlets including Wired, STATNPR, Washington Post and Science Magazine. As part of the MedSeq project, 100 healthy adults were recruited by 9 primary care providers (PCP), themselves briefed on genomics and how to refer patients to genetics experts. All patients gave a detailed family history (FH) but were randomized to get either whole genome sequencing (WGS) (WGS +FH) or not (FH) and were surveyed at 6 months regarding follow-up care and well-being. The study authors uncovered monogeneic disease risk (MDR) variants in 11 patients, but only 2 manifested the phenotype (fundus albipunctatus and subclinical porphyria). 48 of 50 subjects had a pharmacogenetic variant in a gene affecting one of five drugs (warfarin, clopidogrel, simvastatin, metformin, and digoxin) and results were added to electronic health records (EHR). PCPs recommended new clinical actions in 16% and 34% of FH and WGS+ FH patients, respectively. At 6 months, 30% and 41% of patients made health behavior changes in the FH and WGS-FH groups, respectively, but no significant differences in self-reported health, anxiety or depression scores emerged between groups. Overall, the authors conclude that identification of MDR variants did not improve short-term health outcomes, and results do not support the routine use of WGS in healthy patients. However, the authors note that the ability of PCPs to adequately manage patient results, their use of EHR, and their appropriate referrals to genetic specialists, as well as self-reported patient well-being after receiving results are encouraging signs that indicate a favorable environment for WGS in future studies and specific clinical care situations.

You can read the study here and more information about the pharmacogenetics of warfarin, clopidogrel, simvastatin, metformin, and digoxin is available at PharmGKB. 

Wednesday, June 28, 2017

Pharmacogenomics on Nightly News with Lester Holt

The Wednesday, June 28th edition of the Nightly News with Lester Holt featured a short segment on pharmacogenomics.

The piece briefly covered the Mayo Clinic's work in expanding the use of pharmacogenomics in the clinic. Dr. Richard Weinshilboum, co-director of the pharmacogenomics program at the Mayo Clinic, was also interviewed. Dr. Weinshilboum is a leader in the field, and has been a co-author on a number of PharmGKB publications, including multiple PharmGKB pathways and VIPs, as well as the International SSRI Pharmacogenomics Consortium (ISPC) publication. He is also a member of the Pharmacogenomics Research Network (PGRN); PharmGKB is a partner of the PGRN.

PharmGKB provides a page for clinically relevant pharmacogenomic summaries - a list of clinical annotations that contain variant-drug combinations featured in a guideline published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) or other medical society, or implemented at a PGRN site or a major health system, such as the Mayo Clinic. This includes associations such as codeine and CYP2D6 or thiopurine drugs and TPMT; both of these associations have CPIC guidelines. The page also features variant-drug combinations that have a preponderance of evidence showing an association, and therefore may be clinically actionable, but are not currently featured in a guideline.

Tuesday, June 20, 2017

AMIA 10x10 Virtual Pharmacogenomics course with Stanford University begins June 26, 2017

The American Medical Informatics Association (AMIA) has partnered with the Biomedical Informatics program at Stanford University to present an online course in pharmacogenomics (PGx) as part of the AMIA 10 x 10 series. The course, Pharmacogenomics, will  introduce the field and cover topics relevant to PGx including pharmacology, genomics, genome wide association studies (GWAS) and high-throughput assay analyses, natural language processing (NLP), PGx resources such as PharmGKB, Drugbank and NCBI, relevant gene and drug classes as well as current challenges to the implementation of PGx testing in clinical care.  

Russ Altman, MD, PhD, Professor of Bioengineering, Genetics, Medicine, and Computer Science and Director of the Biomedical Informatics Training Program and Co-PI of PharmGKB is also the Director of the 10 x 10 Pharmacogenomics course. Additional instructors include Dr. Michelle Whirl-Carrillo, Associate Director of PharmGKB, Dr. Alison Fohner, former Scientific Curator at PharmGKB, Sara Hillenmeyer, and Dr. Natalia Khuri. 

The course begins June 26th. To learn more and to register, please click here

Tuesday, June 13, 2017

The Next Look for PharmGKB

PharmGKB is excited to show you our all-new website design. We’ve been working hard for months to create a new user interface that serves all of PharmGKB’s content in a clear and flexible way.

You can see the new design by visiting

The “next” site uses modern web technologies and frameworks to produce a clear interface no matter which device you’re using. This means mobile & small-screen devices will have a first-class user experience.

We’re using the new to power this next design. Page load speeds have increased dramatically especially when it comes to our most annotated genes like CYP2D6 and G6PD.

We’d love to know what you think of the new design! Please go to, use the site, and give us your feedback. Every message you send helps us understand how to help people looking to learn more about pharmacogenomics and precision medicine.

We plan to run as a preview of things to come while still showing our traditional design at After a short trial period we will move the “next” design over to

If you have something you’d like us to know about the redesign, please use the feedback button on the bottom-right of any page.

We hope you find this new design as exciting and useful as we do. We look forward to your feedback!

Thursday, June 1, 2017

Curators' Favorite Papers

Concordance between Research Sequencing and Clinical Pharmacogenetic Genotyping in the eMERGE-PGx Study
Authors: Rasmussen-Torvik LJ, Almoguera B, Doheny KF, Freimuth RR, Gordon AS, Hakonarson H, Hawkins JB, Husami A, Ivacic L, Kullo IJ, Linderman MD, Manolio TA, Obeng AO, Pellegrino R, Prows CA, Ritchie MD, Smith M, Stallings SC, Wolf WA, Zhang K, Scott SA.

A new paper in “The Journal of Molecular Diagnostics” examines whether “orthogonal confirmation” of next generation sequencing (NGS) results is necessary. The authors examined data from subjects enrolled as part of the Electronic Medical Records and Genomics Pharmacogenomics (eMERGE-PGx) study. The authors found that for 4077 patients (and 67,900 variants) the per-sample concordance rate was 0.972, while the per-variant concordance rate was 0.997. Source of error for the NGS sequencing results were attributed to the accidental swapping of samples. The source of error in clinical genotyping was attributed to the presence of rare variants near primer annealing sites which may have disrupted hybridization and led to amplification of the other allele ("allele drop-out"). The authors conclude that high concordance between the two sequencing modalities obviates the need for orthogonal sequence confirmation in NGS samples and that concordance could be improved by implementing practices known to further reduce error. 

Drugs in space: Pharmacokinetics and pharmacodynamics in astronauts
Authors: Johannes Kasta, Yichao Yua, Christoph N. Seubertb, Virginia E. Wotringc,d, Hartmut Derendorfa,

A review in “The European Journal of Pharmaceutical Sciences” discusses factors that may affect drug pharmacokinetics and pharmacodynamics, as well as drug safety and efficacy in a very particular situation: space. In addition to the expected effects of microgravity on drug absorption, distribution, metabolism, and elimination (ADME), studies in space have also shown that drug stability, the immune system, and bacterial growth patterns are also affected by microgravity and all must be taken into consideration to ensure drug efficacy and safety during spaceflight. 

Wednesday, May 24, 2017

IGNITE Network Analysis of Genomic Medicine Implementation Published in BMC Medical Genomics

A new paper in BMC Medical Genomics describes a multi-case study of six IGNITE (Implementing GeNomics In pracTicE) network sites currently implementing genomics, including pharmacogenomics, into patient care. The authors discuss challenges to implementation as well as subsequent strategies to address those challenges. 

All participating IGNITE institutions cited low prioritization of genomic data integration into electronic health records (EHR) as a challenge to implementation and four sites addressed this challenge with data warehousing techniques. An additional challenge was the unfamiliarity of many health care providers with interpretation and implementation of genomic data into patient care, which several institutions addressed with the development of educational materials for healthcare providers, facilitation of educational meetings and workshops targeted to physicians as well as stakeholders at various levels, and educational outreach with trained specialists to assist providers in clinical settings. The third most commonly cited challenge was engaging and informing patients. All IGNITE sites utilized various media platforms (e.g. local and national TV and radio, social media, newspapers) to disseminate information about genomic medicine research. Additional strategies included seeking patient input at panels, encouraging patients to assist with the development of educational materials, as well as teaching patients about evidence-based clinical decisions to help them become active in their own care.

You may read the article in its entirety here

Challenges and strategies for implementing genomic services in diverse settings: experiences from the Implementing GeNomics In pracTicE (IGNITE) network.
BMC Medical Genomics May 22, 2017

Nina R. Sperber, Janet S. Carpenter, Larisa H. Cavallari, Laura J. Damschroder, Rhonda M. Cooper-DeHoff, Joshua C. Denny, Geoffrey S. Ginsburg, Yue Guan, Carol R. Horowitz, Kenneth D. Levy, Mia A. Levy, Ebony B. Madden, Michael E. Matheny, Toni I. Pollin, Victoria M. Pratt, Marc Rosenman, Corrine I. Voils, Kristen W. Weitzel, Russell A. Wilke, R. Ryanne Wu and Lori A. Orlando

Tuesday, May 23, 2017

CPIC Survey Available Online

An important function of CPIC (Clinical Pharmacogenetics Implementation Consortium) is to receive feedback from, and give feedback to, our user communities.  CPIC has posted a survey that is part of that feedback and contains questions regarding priorities for CPIC guidelines, as well as feedback on SNOMED CT term submissions.  CPIC requests completion of the survey by May 31st:

Tuesday, May 16, 2017

Voriconazole and Macrolide Antibiotic Pathways featured on PG&G Covers

PharmGKB was pleased to see our pathways featured on two successive covers of the journal Pharmacogenetics and Genomics. Our macrolide antibiotic pharmacokinetics and pharmacodynamics pathway was featured on the cover of the April issue, and our voriconazole pharmacokinetics pathway was featured on the cover of the May issue. PharmGKB curators Dr. Alison Fohner and Julia Barbarino were the respective lead authors on these pathways.

Voriconazole is an antifungal agent used primarily in immunocompromised patients, such as those undergoing organ transplantation. CYP2C19 is the primary enzyme responsible for voriconazole metabolism, and the metabolism and clearance of voriconazole are influenced by CYP2C19 genotype. The voriconazole pathway can be viewed on the PharmGKB website. The Clinical Pharmacogenetics Implementation Consortium (CPIC) also recently released guidelines for voriconazole dosing based on CYP2C19 genotype.

Macrolides are a class of broad spectrum antibiotics of large molecular size, including erythromycin, clarithromycin and azithromycin. Macrolide antibiotics exhibit a number of pharmacogenetic associations with the genes encoding drug transporters and metabolizing enzymes. More information can be found on the macrolide pathway on the PharmGKB website.

Wednesday, May 3, 2017

NHGRI’s Genomic Medicine X: Pharmacogenomics Meeting

On May 2 and 3, 2017, the National Human Genome Research Institute (NHGRI) held its 10th Genomic Medicine meeting, focusing on pharmacogenomics.

PharmGKBPharmCAT and CPIC were presented, as well as a review of the deposition of PharmGKB and CPIC data to ClinVar.  We thank Mary Relling from St Jude Children's Research Hospital,  Marylyn Ritchie from Geisinger and Heidi Rehm from Parnters for highlighting these activities at the meeting.

Wednesday, April 26, 2017

Curators' Favorite Papers

Electronic medical record-integrated pharmacogenomics and related clinical decision support concepts
Authors: Caraballo PJ Bielinski SJ St Sauver JL Weinshilboum RM

The authors of this article from Clinical Pharmacology and Therapeutics, discuss the challenges to successful integration of pharmacogenetic/pharmacogenomic (PGx) clinical decision support (CDS) tools into electronic health and medical records (EMR). They provide examples of medical systems that have already done so and they specifically highlight the success of the Mayo Clinic where CDS tools for eleven PGx genes and nineteen drug-gene interactions have been successfully integrated into EMRs and patient care.

Celebrating parasites
Authors: Greene CS, Garmire LX, Gilbert JA, Ritchie MD, Hunter LE.

This correspondence to Nature Genetics is a response to a controversial 2016 editorial from the the New England Journal of Medicine in which the term, “research parasites” was coined. The term described those researchers who do secondary analyses of data generated by other researchers. The authors argue that “parasites” serve an important purpose in research and that the critical re-analysis of data is crucial for the practice of science. To honor such research, they announce two inaugural award categories at this year's Pacific Symposium on Biocomputing: the Junior Parasite Award and the Sustained Parasite Award.

Sunday, April 23, 2017

March for Science

On April 22, 2017 — members of the PharmGKB team, participated with thousands of other scientists and non-scientists alike, in the March for Science. Please join us, as did Russ Altman (Co-Prinicipal Investigator, PharmGKB) and the larger scientific community in the continuation of evidence-based science.

Monday, April 17, 2017

Thiopurine Pathway updated with new candidate genes

Thiopurines and TPMT have long been a cornerstone of PGx research. As such the Thiopurine Pathway was one of the earliest pathways in PharmGKB to be published in Pharmacogenetics and Genomics [PMID:19952870]. In collaboration with Jun Yang, Takaya Moriyama and Rina Nishii from St Judes, we have substantially updated the Thiopurine Pathway to include new candidate genes in particular NUDT15. NUDT15 will also be featured in a new VIP summary next month. 

The new Thiopurine Pathway figure focuses more on the drug metabolites (which are clickable and linked to Pubchem structures and publications) and candidates for their formation. We have also updated the text to include the kind of summary and literature review PharmGKB pathways are known for, and have a more detailed underlying set of components to allow for data export/analysis. 

Monday, April 10, 2017

Sorafenib pathways published in Pharmacogenetics and Genomics

The PharmGKB review of the Sorafenib pathways has been published in the journal Pharmacogenetics and GenomicsSorafenib (NEXAVAR®, BAY43-9006) is an oral anti-cancer drug approved for the treatment of metastatic or advanced liver, kidney, and thyroid cancers.  Although many new targeted therapies have been tested over the past decade, sorafenib remains the standard of care for these diseases due to its modest efficacy and acceptable tolerability. In this review, we discuss the pharmacokinetic and pharmacodynamic properties of sorafenib and highlight genetic variations that may contribute to the diverse pharmacological responses to sorafenib. 

Find out more...
View interactive pathways on PharmGKB:
Sorafenib Pharmacokinetics Pathway
Sorafenib Pharmacodynamics Pathway

Read our new publication:
Pharmacogenet Genomics. 2017 Mar 30
Gong Li, Giacomini Marilyn M, Giacomini Craig, Maitland Michael L, Altman Russ B, Klein Teri E

PMID: 28362716

View all pathways on PharmGKB.