New pathways on PharmGKB

The following pathways have been recently released on PharmGKB:

Acenocoumarol Pharmacokinetics

Phenprocoumon Pharmacokinetics

Piroxicam Pharmacokinetics

Siponimod Pharmacokinetics/Pharmacodynamics

Aminoglycoside Ototoxicity, Adverse Drug Reaction

These pathways cover gene-drug pairs which have been assigned level A or B by CPIC.A full list of PharmGKB pathways can be found at https://www.pharmgkb.org/pathways

PharmGKB User Survey

We have launched a user survey to help inform the future direction of PharmGKB. All user responses are greatly appreciated; no matter who you are, where you are in the world or how many times you have used PharmGKB. The survey is split into two parts. The first section takes ~1 minute to complete. If you have time to give us some more information, the second section will take an additional ~5 minutes. Thank you for your contribution.

SLCO1B1 added to PharmVar

PharmVar and PharmGKB are excited to share that SLCO1B1 nomenclature is now maintained by PharmVar. This important drug transporter, also known as OATP1B1, has been shown to facilitate the uptake of stains into the liver. Furthermore, genetic variation has been shown to cause musculoskeletal symptoms impeding statin effectiveness.

Star nomenclature has been used by manuscript authors in the past; allele designations were, however, self-assigned and there was no central repository providing oversight or keeping track of the reported allelic variants. The PharmVar SLCO1B1 gene experts have systematically reviewed and curated all information available in the literature. As the published star allele designations were not necessarily consistent in regard of criteria used for their definition, several alleles were merged and/or revised. In addition, new information gathered by the PharmVar Team were utilized to confirm published allele definitions, fill data gaps to facilitate updating some of the existing definitions, as well as discover novel haplotypes adding star alleles to the collection. Specific details of changes to allele definitions can be found on the PharmVar SLCO1B1 page and on the Change Log tab of the SLCO1B1 Allele Definition Table available from PharmGKB.

PharmGKB, PharmVar and CPIC have coordinated updates to their SLCO1B1 resources to reflect its release in PharmVar. The PharmVar SLCO1B1 gene page includes new allele functions assigned by CPIC as part of its forthcoming update to the guideline on SLCO1B1 and statins. These new PharmVar allele definitions and CPIC functions have been incorporated into the CPIC database and implementation resources for use with the current simvastatin guideline recommendations. All resources available through PharmGKB have also been updated accordingly. Standardized nomenclature for this drug transporter is an important step forward for clinical implementation of stain pharmacogenetics.

PharmGKB announces the launch of PharmGKB Pediatric

PharmGKB Pediatric (https://pediatric.pharmgkb.org) is a "view" of PharmGKB (https://www.pharmgkb.org) that highlights pharmacogenomic annotations that (1) are based on pediatric studies or (2) may be relevant to pediatrics.  All of the annotations found on PharmGKB are also on PharmGKB Pediatric.  

A quick way to access pediatric information is to click the blue "Pediatric Pharmacogenomics" button on the website homepage 

                           

and follow the link to the "Pediatric Annotations Dashboard".  

This dashboard gives an overview of what percentage of each type of PharmGKB annotation has pediatric information. 

A description of how annotations qualify for the pediatric tag can be found here.  Clicking on the link under a pie chart will take the user to a complete list of pediatric annotations that can be sorted, filtered or downloaded.

Also on PharmGKB Pediatric, the menu on the left-hand side of drug and gene page will have a "child" icon if there are pediatric annotations in a particular category (see example below).  Additionally, manually-curated summaries of the pediatric annotations and pediatric information from FDA-approved drug labels (see example below)

Example screenshot of warfarin page with pediatric icons and summary.

are available for over 80 drugs (as of 11 October 2021) that fall into these categories:  (1) CPIC guideline drugs and (2) drugs on the Best Pharmaceuticals for Children Act (BPCA) priority list AND that have at least one pediatric variant annotation.  

We continue to add to the list of drugs with pediatric summaries and develop the site for users.

NIH Request for Information on Scientific Data Sources

The U.S. National Institutes of Health (NIH) has put out a Request for Information (RFI) on User Experience with Scientific Data Sources and Tools in order to better understand the use of these resources by the scientific community.

We’re asking the pharmacogenomics community to consider responding to the survey and show their support for pharmacogenomics resources like PharmGKB and PharmVar. The RFI closes on October 15.

PharmCAT Version 1.0 Released

Version 1.0 of the Pharmacogenomics Clinical Annotation Tool (PharmCAT) has been released today (September 27, 2021). PharmCAT is a software tool that takes genetic data for an individual as VCF file input, interprets the pharmacogene alleles, diplotypes and phenotypes, and generates reports with CPIC's genotype-based drug prescribing recommendations which can be used to inform treatment decisions. This is the first official release of PharmCAT and it contains multiple updates to the previously published beta version.

Expanded coverage

Version 1.0 extends the coverage of alleles in existing PharmCAT genes and adds more genes, drugs and guidelines from CPIC. Content is sourced from the CPIC database. The PharmCAT site includes a list of genes and drugs (along with prescribing recommendations) included in the report.

New input and output options

v1.0 of PharmCAT enables the input of diplotypes determined by tools or genetic testing reports outside of PharmCAT to be used to predict gene phenotypes and retrieve respective CPIC recommendations. Previously, only “outside” calls for CYP2D6 diplotypes were allowed, but now diplotypes for any gene supported by PharmCAT can be supplied. For example, if you have a CYP2C9 diplotype call in hand, you can input that to PharmCAT so the CYP2C9 phenotype and CPIC recommendations are included in the final report.

The section of PharmCAT that takes diplotype calls and predicts phenotypes (e.g. metabolizer phenotypes) has been encapsulated into its own module. The "phenotyper" module allows for the input of phenotypes determined outside of PharmCAT, such as from genetic testing reports, to be used to retrieve CPIC recommendations. For example, if you have already determined a CYP2C9 phenotype, you can input that to PharmCAT so the CYP2C9 CPIC recommendations for that phenotype will be included in the final report.

The separation of the “phenotyper” code into its own module also means that if you are only interested in predicting pharmacogene diplotypes and/or phenotypes from a VCF file, you can get that information without proceeding to the final human-readable report.

More PharmCAT validation testing

v1.0 has dramatically expanded in silico testing for internal validation of PharmCAT allele matching. We have created a testing system that generates VCF files to match against expected results and report any mismatches. This system successfully tests the NamedAlleleMatcher beyond the published validation in our paper published in January 2020.

VCF preprocessor

We now provide a VCF preprocessor tool to prepare VCF files for the named allele matcher. PharmCAT requires the input VCF to follow the official VCF format specifications (version 4.1 or later) and expects a parsimonious variant representation format to avoid ambiguity. However, user-supplied VCF files may not always follow the official VCF format specifications and can represent genetic variants in different representation formats as a result of varied VCF preparation bioinformatics pipelines. Variant representation formats different from PharmCAT's requirements can cause unexpected technical hurdles and will require additional data preparation. To resolve this issue, PharmCAT provides a VCF preprocessor tool to normalize and prepare VCFs to a format readily digestible by PharmCAT. The VCF preprocessor will automatically download the Human Reference Genome Sequence fasta and index files from the NIH FTP site to normalize genetic variants in VCF. Preprocessed VCF data will include only necessary PGx allele defining positions, which will improve PharmCAT's runtime. Users will also receive a report VCF of missing PGx positions in the original VCF file.

Future releases

Development of PharmCAT continues! You can expect more releases very soon as we gather feedback from this release and issue more updates to underlying data coming from CPIC and PharmVar.

New features will also include multi-sample VCF support, GVCF support, and FHIR-formatted reports. Keep an eye on the releases page for updates.

PharmGKB Tutorial Published

We are pleased to announce that an updated PharmGKB tutorial has now been published in Current Protocols.

The paper describes how to navigate the PharmGKB website to retrieve information on how genes and genetic variations affect drug efficacy and toxicity. It also includes a protocol on how to use PharmGKB to facilitate interpretation of findings for a specific pharmacogenomic variant genotype or metabolizer phenotype. 

Further information about how to use PharmGKB, including a short guided page tour and training exercises, can be found on our website.