Retirement of CYP3A5 alleles in PharmVar

The PharmVar CYP3A5 expert panel has undertaken an extensive review of CYP3A5 allelic variation which led to the retirement of three star alleles, namely CYP3A5*2, *4 and *5. Based on new data, their defining variants were always found together with the CYP3A5*3-defining splice defect (c.219-237) meaning that their variants are part of CYP3A5*3 haplotypes and do not occur on their own as previously assumed.  Specifically, c.1193C>A (formerly defining CYP3A5*2) is now part of the CYP3A5*3.010 suballele, c.599A>G (formerly defining CYP3A5*4) is now part of the CYP3A5*3.009 suballele, and c.432+2T>C is part of the CYP3A5*3.005 suballele which has first been described in 2003 as published as CYP3A5*3G.

This update makes genotype testing and analysis simpler moving forward. CYP3A5*2, *4 and *5 no longer need to be tested as they are tagged by the CYP3A5*3 variant and thereby accurately identified and reported as CYP3A5*3. Note that in the past, a patient who tested homozygous for c.219-237 (CYP3A5*3) and heterozygous for c.1193C>A (CYP3A5*2) may have been reported as having a CYP3A5*3/*3+*2 diplotype.

 

This update on CYP3A5 nomenclature is now shown on the PharmVar CYP3A5 page and is described in more detail in the PharmVar CYP3A5 GeneFocus review published in Clinical Pharmacology and Therapeutics.

 

PharmGKB, CPIC and PharmCAT have been updated accordingly to reflect this change.

Update to individual statin pathways to support release of new CPIC guidelines for statins

To coincide with the release of the updated CPIC guidelines for SLCO1B1, ABCG2 and CYP2C9 and statin-associated musculoskeletal symptoms, we have updated the statin pharmacokinetic (PK) pathways. We now have one PK pathway for each individual drug in the guideline and have added details of the specific metabolites as well as the candidate genes and references. 

Atorvastatin Pathway, Pharmacokinetics

Fluvastatin Pathway, Pharmacokinetics

Lovastatin Pathway, Pharmacokinetics

Pitavastatin Pathway, Pharmacokinetics

Pravastatin Pathway, Pharmacokinetics

Rosuvastatin Pathway, Pharmacokinetics

Simvastatin Pathway, Pharmacokinetics

Note: If you have visited pathways recently you may need to refresh your browser or empty cookies to see the updated versions. Plus the history log at the bottom of the pathway lets you know if you are seeing the most updated version. 

CPIC Publishes Guideline for SLCO1B1, ABCG2, CYP2C9 and Statin Therapy

The CPIC guideline for SLCO1B1, ABCG2, and CYP2C9 and statin-associated musculoskeletal symptoms (SAMS) has been published in the journal Clinical Pharmacology and Therapeutics. This guideline is an update to the CPIC guideline for simvastatin and SLCO1B1, but now includes expanded literature review on four additional genes, ABCG2, CYP2C9, HMGCR and CYP3A4/5 and all statins. 

The guideline gives specific prescribing recommendations for: 

• simvastatin, atorvastatin, lovastatin, pravastatin and pitavastatin based on SLCO1B1 phenotype
• rosuvastatin based on SLCO1B1 and ABCG2 phenotypes 
• fluvastatin based on SLCO1B1 and CYP2C9 phenotypes 

It also provides a figure illustrating statin recommendations with preferred statin intensity and statin dose stratified by SLCO1B1 phenotype (i.e., decreased or poor function):

For therapeutic recommendations and further details, please refer to the guideline and supplemental materials on the CPIC website. Annotations of the guideline, including interactive genotype picker tool for each statin, is available on the PharmGKB website.

Registration opens for CPIC-PGRN 2022 meeting in Denver, Colorado

We are excited to announce that registration is open for the 2022 CPIC-PGRN meeting: Diversifying PGx Science to Improve Implementation. The meeting will be held at the University of Colorado on May 10^th, 11^th, and 12^th in Denver, CO. Registration, agenda, and hotel information available at the meeting website. Early bird registration is now open and is $250.00.  The deadline for early bird registration is April 1, 2022. Regular registration will open April 2, 2022 and is $350.00.  The deadline to register is May 1, 2022. 

We are keeping an eye on the COVID status and will abide by the restrictions and guidelines set by the University of Colorado at the time of the meeting. We are planning a COVID “rain date” in case we need to reschedule the meeting. If the meeting is cancelled due to COVID, registration fees will be refunded. No virtual option will be available.

 

The draft agenda can be found on the meeting website. We are still finalizing final titles and speakers and we will post the final agenda once complete.

 

Participants are invited to submit abstracts for the poster sessions.  Please send your abstract to CPIC-PGRN2022@pgrn.org. Acceptance notifications and guidelines will be sent prior to the early registration deadline (April 1^st). 

 

Abstract Submission guidelines:

Final Submission Deadline: March 18th, 2022 

Required Sections:  Authors, Institutions, Background, Methods, Results, Conclusions

1 figure or table may be included

Word limit: 500 words

Please note that submitting an abstract does not register you for this meeting. 

 

Hope to see you there! If you have any questions about registration, please email kelly.caudle@stjude.org. 

 

Best wishes,

Kelly Caudle and Teri Klein (CPIC co-PIs)

PharmGKB Heparin-Induced Thrombocytopenia Pathway published

A PharmGKB pathway of heparin-induced thrombocytopenia (HIT) has been published in Pharmacogenetics and Genomics.

Heparin is a commonly used anticoagulant. The pathway, written by Elise Miller along with other members of the Karnes lab at the University of Arizona as well as members of the PharmGKB team, outlines the atypical immune response which can occur in some patients receiving heparin. HIT can have a mortality rate of up to 30% and shares some similarities with COVID-19 while patients with COVID-19 have been found to be at an increased risk of HIT. Pharmacogenomics research has identified some candidate biomarkers, particularly in immune system receptors, which may affect a patient’s risk of experiencing HIT, however further work is needed to validate these and discover other candidates.

 

An interactive version of the pathway can be found on the PharmGKB website.