Tuesday, November 10, 2020
In the sections pharmacogenomic mechanisms, pharmacogenomic evidence and guidelines for psychiatry, and pharmacogenomic testing in psychiatry the review provides an up-to-date summary of recent developments that clinicians should know when considering PGx testing for their patients. It summarizes and discusses the evidence that was considered by the International Society of Psychiatric Genetics (ISPG) for a statement about “Genetic testing and psychiatric disorders” updated in 2019.
The author group concludes that PGx testing should be viewed as part of the decision supporting measures to assist implementation of good clinical care, highlighting CYP2D6, CYP2C19, HLA-A, and HLA-B. For further details read the review [PMID: 33147643].
Thursday, November 5, 2020
Clinical Pharmacogenetics Implementation Consortium (CPIC) has released the first version of its database and API to the public. The CPIC database is a relational database containing data from CPIC's guidelines in structured formats. These data include the guideline manuscript recommendations and information from all of the supporting guideline tables, including gene variant and allele frequencies, function assignments, definitions, diplotype-phenotype mappings and example CDS (clinical decision support) language, as well as example drug-based pre- and post-test alerts and CDS flow charts. Mappings of CPIC gene and drug names to multiple vocabularies/terminologies are also available. The CPIC database can be accessed through the CPIC API or via whole database exports. The API is a RESTful interface and allows access to all parts of the currently defined data model. Documentation for how to use the API with examples can be found in the database documentation. Versioned, whole-database exports can be found in each release on GitHub.
We encourage users to please read the extensive documentation about the data models and formats. Different guideline gene-drug pairs require slightly different models which is explained in the documentation. An understanding of these differences is critical to use the data appropriately. Additionally, each guideline has unique caveats and nuances that can only be fully appreciated by reading the guideline itself, so we encourage users to read the guidelines when accessing and using data from the CPIC database.
We anticipate and encourage user feedback from the community. Please contact us at firstname.lastname@example.org with questions and comments.
Thursday, October 1, 2020
Tuesday, September 29, 2020
The PharmGKB tutorial for pharmacogenomics of drugs potentially used in the context of COVID-19 is now published in Clinical Pharmacology and Therapeutics.
The article is the first in a series of Pharmacogenomics Knowledgebase (PharmGKB) tuto
Using examples of drugs found in the portal the authors demonstrate some of the main features of PharmGKB including guideline, drug label, clinical, and variant annotations.
Wednesday, September 23, 2020
The co-PIs of the Pharmacogenomics Clinical Annotation Tool (PharmCAT). Dr. Marylyn Ritchie of the University of Pennsylvania and Dr. Teri Klein of Stanford University were awarded a three year grant from the National Institutes of Health National Human Genome Research Institute (NIH NHGRI) to continue and expand the project. PharmCAT was originally created in 2016 and is a tool that: (1) extracts variants found in CPIC guideline genes from a sequencing or genotyping Variant Call Format (VCF) file, (2) assigns star alleles, diplotypes and drug phenotypes based on slightly modified PharmVar core alleles in CPIC/PharmGKB definition tables and CPIC allele function and phenotype tables, and (3) provides an HTML/PDF report including CPIC genotype-based drug prescribing recommendations.
We published the initial assessment of PharmCAT in Clinical Pharmacology and Therapeutics in 2019 (PMID: 31306493) and the beta version is currently available for testing. Due to limited resources, PharmCAT has only been tested on a small sample of genotype data and with information from CPIC guidelines as of 2018. The new funding will enable PharmCAT to (1) update to current CPIC guidelines and release version 1.0, (2) create a module for VCF pre-processing and quality control, (3) export an electronic health record (EHR) compatible report using Fast Healthcare Interoperability Resources (FHIR) specifications, and (4) provide the ability to run multiple VCF files at one time (batch processing). We will announce the PharmCAT v.1.0 release on the PharmGKB blog. Check the PharmCAT website to see updates as they happen.
This work is supported by the NIH NHGRI U24HG010862.
PharmCAT workflow below. Yellow boxes are input files for PharmCAT. Blue boxes are PharmCAT modules. Green boxes are PharmCAT module output and input into the next module. Grey boxes are alternate input into PharmCAT.
Tuesday, September 8, 2020
The 2020 CPIC Guideline update for HLA-B, CYP2C19 and phenytoin dosing is now published in Clinical Pharmacology and Therapeutics. The accepted article can be accessed on the PharmGKB page for phenytoin and on the CPIC website.
Phenytoin is an antiepileptic drug with inter-individual pharmacokinetic variability, partly due to CYP2C9 genetic variation, and a narrow therapeutic index. The presence of the HLA-B*15:02 variant allele is associated with an increased risk of phenytoin-induced cutaneous adverse reactions of Stevens-Johnson syndrome and toxic epidermal necrolysis.
Literature published after the 2014 guideline was reviewed and the recommendations and supplemental information were updated. This includes updates to CYP2C9 allele assignments using the activity score (AS) system. The CYP2C9*2/*2 diplotype (AS=1) is now translated into the IM phenotype group (originally translated to PM). This is based on similar effects of CYP2C9*1/*3 (AS=1) and CYP2C9*2/*2 on metabolic ratio and dose requirements for multiple substrates. CYP2C9*3 is classified as ‘no function’ allele with an activity value of 0 for AS calculation.
For therapeutic recommendations and further details including an algorithm for suggested clinical actions based on HLA-B*15:02 and CYP2C9 genotype, please refer to the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C9 and HLA-B Genotypes and Phenytoin Dosing: 2020 Update.
Wednesday, August 26, 2020
PharmGKB and CPIC have formalized a partnership with ClinGen to bring pharmacogenomics (PGx) expertise to the primarily disease-focused, NIH-funded mega-resource. ClinGen's goals include defining the clinical relevance of genes and variants for use in precision medicine and research and disseminating that knowledge to the broader community. They have developed and implemented data standards for clinical annotation and interpretation of genes and variants. To date, this annotation and interpretation has focused on disease-related genes and variants. The partnership with PharmGKB and CPIC was established to bring PGx knowledge to the ClinGen community. Gene-level PGx entries which link to PharmGKB and CPIC will be added to the current validation, dosage and actionability curations displayed on ClinGen so that users will be able to access the PharmGKB and CPIC resources through the ClinGen interface. Planning is underway for the PGx display. Additionally, PharmGKB is working to provide links back to ClinGen for genes and variants associated with disease phenotypes.