CPIC releases updated Genes-Drugs list

Clinical Pharmacogenetics Implementation Consortium (CPIC) has posted an updated Genes-Drug list. Changes include: 

1. A new column was added to the table called “CPIC Level Status”. Assigned CPIC levels have always been considered provisional unless and until the gene/drug pair has been reviewed in the course of a CPIC guideline. All gene-drug pairs reviewed as part of CPIC guidelines have been assigned a “final” assignment; others were assigned “provisional,” and this column designation should clarify this distinction for the user. 

2. CPIC Levels “A/B”, “B/C” and “C/D” have been included in the past, but now these levels have been defined at https://cpicpgx.org/prioritization/#leveldef. 

3. Gene/drug pairs (including some in the FDA’s new PGx association list) were re-evaluated. Some gene-drug pairs were added and some had their provisional levels changed after preliminary review of the evidence and actionability recommended by others. 

4. The previous version of the list contained some drug classes. In this list the drugs have been separated out individually so that classes are no longer listed. 

5. Some gene-drug pairs were removed because on reassessment, they did not meet the criteria for inclusion.

PharmGKB tutorial for pharmacogenomics of drugs potentially used in the context of COVID-19

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) tutorials intended as a resource to help users become quickly acquainted with the wealth of information stored in PharmGKB. 

Each article will center around a specific topic, like in this publication the PharmGKB COVID-19 portal (previously blogged about it here). 

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.

PharmCAT grant awarded

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.

CPIC Guideline update: HLA-B/CYP2C9 and Phenytoin/Fosphenytoin

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.

PharmGKB and CPIC Partner with ClinGen

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.

New CPIC Guideline: CYP2C19 and Proton Pump Inhibitors (PPIs)

The CPIC Guideline for CYP2C19 and proton pump inhibitor (PPI) dosing is now published in Clinical Pharmacology and Therapeutics. The accepted article can be accessed on the PharmGKB page for omeprazole, lansoprazole, pantoprazole, dexlansoprazole, and on the CPIC website. 

PPIs inhibit the final pathway of acid production, which leads to inhibition of gastric acid secretion. PPIs are widely used in the treatment and prevention of many conditions including gastroesophageal reflux disease, gastric and duodenal ulcers, erosive esophagitis, H. pylori infection, and pathological hypersecretory conditions. The first-generation inhibitors omeprazole, lansoprazole and pantoprazole are extensively metabolized by the cytochrome P450 isoform CYP2C19 and to a lesser extent by CYP3A4. The second-generation PPI dexlansoprazole appears to share a similar metabolic pathway to lansoprazole. CYP2C19 genotypes have been linked to PPI exposure and in turn to PPI efficacy and adverse effects.

The CPIC guideline summarizes evidence from the literature and provides therapeutic recommendations for omeprazole, lansoprazole, pantoprazole, dexlansoprazole based on CYP2C19 genotype. For therapeutic recommendations and further details, please refer to the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C19 and Proton Pump Inhibitor Dosing.

CYP3A5 released on PharmVar

PharmVar and PharmGKB are excited to announce that CYP3A5 has been transitioned into the PharmVar database. Variation information has been extensively curated by the PharmVar CYP3A5 gene experts which led to the correction of some allele definitions or reclassification of others. The submission of new data added novel suballeles, as well as helped to raise the evidence levels for several alleles from ‘Lim’ to ‘Def’. Important CYP3A5 information is provided in the ‘Read Me’ document such as reference sequences used and how the PharmVar CAVE tool facilitates comparisons of core allele definitions. All changes and revisions have been summarized in the ‘Change Log’ document. Here we also list all new haplotypes. Check it out at https://www.pharmvar.org/gene/CYP3A5.

And finally, a big thank you to all of the CYP3A5 gene experts who serve on this panel for their hard work.