New tutorial and walkthrough videos now available

We are pleased to announce the release of our PharmGKB walkthroughs and tutorial videos on YouTube. Users can now view detailed video walkthroughs of each of the main annotation types on PharmGKB as well as a longer video combining resources from across the site. We have also produced a series of tutorial videos to help users learn more about key concepts and issues in pharmacogenomics. These videos range from an introduction to the field to an explanation of the star allele nomenclature system for haplotypes. The videos are freely available on the PharmGKB YouTube channel. Links can also be found on our Educational Resources page. 

PharmGKB and Reactome collaborate on two pathways

PharmGKB has collaborated with Reactome for two new pharmacokinetics pathways, Ribavirin, and Prednisone and Prednisolone available via both formats:

Ribavirin Pathway, Pharmacokinetics 

on Reactome 

on PharmGKB

Prednisone and Prednisolone Pathway, Pharmacokinetics 

on Reactome

on PharmGKB

 

Study of vitamin K pathways presents potential new warfarin candidates

Almost two decades after the cloning of VKORC1 and association with warfarin dose, a new pathway of vitamin K cycling has been published. Mishima et al [PMID:35922516] report on the Ferroptosis suppressor protein 1 (FSP1), coded for by the AIFM2 gene, and its mechanism of maintaining vitamin K in the hydroquinone form. While not interacting directly with warfarin, AIFM2 may play a role in vitamin K-related branches in the warfarin PD pathway that warrant investigation for PGx. 

A review of several ferroptosis related proteins (Vabulas, 2021) discusses some variants of AIFM2. The review mentions a functional study of E156A in the FAD cofactor binding domain that found it impaired anti-ferroptotic activity. This variant is not found in dbSNP. A different amino acid change, E156D (rs1272224219C>A), has not been observed in the ALFA populations that dbSNP reports on, while yet another amino acid change, E156V (rs760393626T>A), is extremely rare (found in 1/121216 alleles). The review lists 2 other potential AIFM2 candidates for functional investigation which are more frequently observed: M135T (mapped by PharmGKB to rs10999147A>G) and D288N (mapped to rs2271694C>T).

(Edited 9/20/22) The Warfarin Pathway, Pharmacodynamics has been updated to include the new candidate gene.

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PharmVar GeneFocus paper for SLCO1B1 is published

The PharmVar GeneFocus: SLCO1B1 paper has just been published by Clinical Pharmacology & Therapeutics.

 

This review provides a general overview of SLCO1B1 as well as a deeper dive into its nomenclature. This GeneFocus covers genetic variability, functional impact, clinical relevance, gene nomenclature before and after PharmVar updates, methods for allele characterization and how the new nomenclature impacts pharmacogenetic testing and interpretation. 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. This new nomenclature has been used in the recently published CPIC guideline on statin-associated musculoskeletal symptoms.

 

For more details, please see:

PharmVar GeneFocus: SLCO1B1

Clin Pharmacol Ther. 2022 Jul 7. doi: 10.1002/cpt.2705. 

Laura B. Ramsey, Li Gong, Seung-been Lee, Jonathan B. Wagner, Xujia Zhou, Katrin Sangkuhl, Solomon M. Adams, Robert J. Straka, Philip E. Empey, Erin C. Boone, Teri E. Klein, Mikko Niemi, Andrea Gaedigk.

PMID: 35797228

CYP2A6 now released on PharmVar

PharmVar and PharmGKB are excited to share that CYP2A6 has been transitioned into the PharmVar database. CYP2A6 metabolizes several substates including coumarin, nicotine, aflatoxin B1, nitrosamines, and some pharmaceuticals. Owing to its highly polymorphic nature, CYP2A6 activity varies considerably between individuals. Due to the complex nature of the CYP2A gene locus that contains not only CYP2A6, but also the highly similar CYP2A7 and CYP2A13 genes, CYP2A6 genotype analysis and characterization of allelic variants is not trivial. It is therefore of utmost importance to have up-to-date information regarding sequence variation and star allele (haplotype) definitions to facilitate accurate genetic testing, data interpretation and phenotype prediction in the research and clinical settings.  

The PharmVar CYP2A6 gene experts have systematically reviewed and curated all star allele definitions that were previously issued by the CYP450 Nomenclature databases (these were last updated in 2014 and can be accessed through the archive). Some notable changes include:

• Variants and star alleles are now defined using the most current genomic reference sequence
• Several alleles have been merged, revised and/or redesignated (legacy allele designations are cross-referenced)
• Regions used for allele definitions have been updated
• Structural variants including a common conversion at the 3’UTR have been updated to current knowledge and are detailed in the ‘Structural Variation’ document.

Changes made are detailed in the ‘Change Log’ document and other important information about CYP2A6 and the information displayed by PharmVar can be found in the ‘Read Me’ document. All accompanying documents can be accessed at the PharmVar CYP2A6 page at https://www.pharmvar.org/gene/CYP2A6.  

 

Since there are no CPIC guidelines for CYP2A6, the PharmVar CYP2A6 page does not provide information for ‘CPIC clinical function’. The expert panel has, however, compiled a table in the ‘Read Me’ document summarizing function information for selected star alleles.  

 

Lastly, we would like to thank the PharmVar CYP2A6 experts Rachel Tyndale, Alec Langlois, Meghan Chenoweth, Giada Scantamburlo, Charity Nofziger, David Twesigmwe, Rachel Huddart and Andrea Gaedigk for their tireless efforts that made this massive update possible.

Clinical Genomics Career Panel webinar series 2022

ClinGen is hosting a Clinical Genomics Career Panel webinar series this summer for individuals interested in career in clinical genomics. Sessions are moderated and panel members will discuss their work and career paths. All are welcome to join!

PharmGKB Acyclovir/Ganciclovir Pathway Published

The PharmGKB Acyclovir/Ganciclovir Pathway has recently been published in the journal Pharmacogenetics and Genomics.

Acyclovir (ACV) and ganciclovir (GCV) are commonly prescribed antivirals to treat infections caused by herpes viruses, varicella-zoster virus or cytomegalovirus (eg. cold sores, shingles and chicken pox, etc.). The pathway, co-developed by Maud Maillard along with other members of the Yang Lab in St. Jude, as well as members of the PharmGKB team, outlines the metabolism, transport, and mechanism of action of ACV and GCV with a view to decipher the existing interpatient variability, and highlights pharmacogenomics implications by the variants of the NUDT15 and ABCC4 genes on ACV and GCV efficacy.  Further work is needed to validate these findings and discover other candidates, with the aim of optimizing antiviral therapy.

 

View the interactive pathway on PharmGKB:
Acyclovir/Ganciclovir Pathway, Pharmacokinetics/Pharmacodynamics

 

Read our new publication:

PharmGKB summary: acyclovir/ganciclovir pathway
Maud Maillard, Li Gong, Rina Nishii, Jun J Yang, Michelle Whirl-Carrillo, Teri E Klein
Pharmacogenet Genomics. 2022 Jul 1;32(5):201-208. Epub 2022 May 30.

PMID: 35665708

View all pathways on PharmGKB.