PharmGKB has curated new pathways for the pharmacokinetics of the following drugs that are on the CPIC gene-drug pairs list and either have existing guidelines or are slated for future consideration.
Antidepressant:
Inhaled anesthetics:
NSAIDs:
A complete list of PharmGKB pathways can be found at https://www.pharmgkb.org/pathways
The CPIC guideline for aminoglycoside antibiotics and variation in the mitochondrial gene MT-RNR1 has been published in the journal Clinical Pharmacology and Therapeutics.
Aminoglycosides are widely used antibiotics which inhibit protein synthesis in bacteria by binding to the bacterial 16S ribosomal subunit. They are also associated with adverse events, including aminoglycoside-induced hearing loss (AIHL). Patients who carry certain variants in the MT-RNR1 gene, which encodes the 12S ribosomal subunit, are at a greatly increased risk of developing AIHL. These variants cause the 12S subunit to more closely resemble the bacterial 16S subunit, which can lead to aminoglycoside molecules binding to the ribosome and inhibiting protein synthesis. This ultimately results in hearing loss due to cell death in the cochlea.
This is the first CPIC guideline on a mitochondrial gene. As the mitochondrial genome is haploid, rather than diploid, recommendations are given for single variants, rather than for combinations of alleles.
The guideline and supplemental materials are available on the CPIC website. An annotation of the guideline, including interactive genotype picker tool, is available on the PharmGKB website.
PharmGKB and CPIC recently hosted a Twitter chat sharing pharmacogenomics resources as part of NHGRI's Healthcare Providers Genomics Education week (#MedGeneEd21). An archive of the chat is displayed below.
#MedGeneEd21 PGx chat - Curated tweets by pharmgkbThe Proton Pump Inhibitor Pathway, Pharmacokinetics has been updated and expanded to now highlight four pathways with candidate genes and drug metabolites involved for:
Lanzoprazole and dexlansoprazole,
Pantoprazole and
The pathways illustrate the subtle differences between the metabolism of drugs in the class, their different sensitivities to variation in CYP2C19, and aids explanation of the differences in CPIC recommendations for the different drugs (see CPIC Guideline for CYP2C19 and Proton Pump Inhibitor Dosing).
We announced last December that the Clinical Pharmacogenetics Implementation Consortium (CPIC) was launching its Term Standardization Pharmacogenetic Test Results - Part 2 project. The project is currently focused on MT-RNR1, as that guideline wraps up.
The MT-RNR1 Gene/Disease and PGx expert panels have agreed on terminology for MT-RNR1 and aminoglycoside-induced hearing loss for allele clinical function and phenotype. The final terms are posted for review on the CPIC website. Please send any feedback to Dr. Kelly Caudle at contact@cpicpgx.org by May 28th, 2021.
The allele pull-down menu (also known as the genotype-picker tool) on PharmGKB annotations of CPIC guidelines is an extremely popular feature among users. We are pleased to now expand this functionality to annotations of guidelines from the Royal Dutch Association for the Advancement of Pharmacy - Pharmacogenetics Working Group (DPWG).
The genotype picker tool relies on determining the following information from each guideline:
1. Which alleles are covered by the guideline
2. The assigned functional status of each allele
3. How allele function combinations are mapped to phenotype groups
The DPWG recommendations that are downloadable from the Dutch Pharmacy Organization’s (KNMP) website and annotated on PharmGKB do not typically contain allele functional status or phenotype group mappings. However, this information is often available in KNMP’s ‘gene background’ files which are posted separately. While DPWG generally follows the same allele-to-phenotype mappings as CPIC, there are some gene-specific differences. These differences mean that all DPWG gene mappings need to be curated into PharmGKB separately from CPIC’s mappings. Our mapping process for each gene covered by DPWG guidelines, including curator notes, can be found here. As we now have internally curated mappings of allele function to phenotype for DPWG, more DPWG guidelines can now be used to support our Level 1A clinical annotations.
Genotype pickers are now available for all annotations of DPWG guidelines with recommendations for HLA-B, CYP2D6 and CYP2C19 genotypes. Work is ongoing to curate DPWG-assigned allele functions and phenotype groups for other genes into PharmGKB. As each gene is curated, genotype pickers will be released on relevant guideline annotation pages.
PharmVar and PharmGKB are excited to announce that CYP3A4 has been transitioned into the PharmVar database. Check it out here.
Numerous changes and revisions have been made during an extensive curation process including limiting the upstream and downstream regions used for allele definitions and the removal of introns of unknown functional consequence; these revisions caused the retirement of several suballeles or merging of suballeles.
In addition, upgrading to the gene’s current reference sequence (NG_008421.1) caused the c.-392A>G SNP to flip to c.-392G>A; in other words, all alleles that previously had the c.-392A>G SNP now match the RefSeq and are thus no longer showing the variant, while all other alleles gained c.-392G>A. Furthermore, the submission of new data added one novel star allele,CYP3A4*35, several novel suballeles, as well as helped to raise the evidence levels for many alleles from ‘Lim’ to ‘Def’.
Important CYP3A4 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 provide a record of novel haplotypes that have been submitted to PharmVar and have been accepted.
Finally, a big thank you to all CYP3A4 gene experts for volunteering their time and expertise!
