Announcement of PharmVar Content Changes

PharmVar continues to evolve and strive to offer high-quality content to our global users. To allow us to bring new clinically relevant content to PharmVar we needed to make some difficult decisions and ‘retire’ several CYP genes. This decision is based on a newly developed points-based rating system (0-100 points) that allows us to prioritize which genes to maintain and which genes to evaluate for future introduction into PharmVar. More detailed information regarding PharmVar gene content and prioritization will be posted under the GENES tab once these changes have taken effect May 12, 2023.

The following genes were not considered pharmacogenes by PharmVar due to their contribution to lipid and steroid metabolism and/or associations with disease and will be retired:  CYP4A11, CYP4A22, CYP4B1, CYP17A1, CYP19A1, CYP21A2, CYP26A1, TBXAS1  and PTGIS (0 points each), though several of these genes have variant and low level clinical annotations on PharmGKB. Other databases such as ClinGen and/or ClinVar may also be consulted for variation annotations. These genes were listed by PharmVar as ‘legacy’ genes. POR (3 points) was also listed as a legacy gene.  The following genes were transitioned into the PharmVar database, but never curated by an expert panel nor any additional data added: CYPs  1A1, 1B1, 2E1, 2F4, 2J2, 2R1, 2S1, 2W1, 3A7 and 3A43. These genes were not deemed to be clinically important pharmacogenes by the PharmVar Steering Committee based on having 0 points in the ranking system and will also be retired. Furthermore, the link to the archived Human Cytochrome P450 (CYP) Allele Nomenclature database record (last version by cypalleles.ki.se in 2017) will be deactivated to discourage use of outdated information (a copy can be requested through support@pharmvar.org).

If new data emerges and rankings change, a gene may be reintroduced to PharmVar. 

 

NAT2 is currently undergoing curation and is anticipated to be transferred from the Databases of Arylamine N-acetyltransferases (NATs) to PharmVar in summer 2023. The introduction of NAT2 into the PharmVar database is timely as CPIC is initiating a guideline for the NAT2/hydralazine gene-drug pair.  Additionally, NAT2 has multiple clinical annotations and mulitple annotated FDA and other regulatory agency labels.

 

As always, PharmVar values your feedback and suggestions support@pharmvar.org.

CYP3A5 genotyping is a more accurate predictor of drug response than race alone

 A new paper in Journal of Clinical Pharmacology from a group at Indiana University [PMID:37042314] implemented genotyping for CYP3A5 in a kidney transplant center.

The team used CPIC guidelines for tacrolimus dosing based on CYP3A5 genotype.

Implementation included provider education and clinical decision support in the electronic medical record.

This study reinforces that CYP3A5 genotype is an important predictor of therapeutic tacrolimus trough concentrations. They demonstrate that CYP3A5 normal and intermediate metabolizers had fewer tacrolimus trough concentrations within the desired range post-transplantation and took longer to achieve therapeutic dose than poor metabolizers. While the authors note they were underpowered to measure outcomes, there was a trend towards transplant rejection or all-cause mortality within the first year of transplant based on CYP3A5 metabolizer phenotype.

The paper highlights how, despite the guidelines from CPIC being published in 2015, the FDA label still currently only has language around race-based dose adjustment rather than giving precise guidance based on genotype:

“The FDA drug label recommends higher starting doses in individuals of African ancestry, but only 70% of African Americans are normal/intermediate metabolizers. CYP3A5 normal/intermediate metabolizers are also found among whites and Asians (East Asian and Central/South Asian) at lower frequencies (14% and 44-55%, respectively).”

“Self-reported African American race is more closely associated with CYP3A5 expresser status than other self-reported race categories, but self-reported race is not an accurate surrogate for genotype.”

The discussion is a reminder that pharmacogenomics can play a key role in reducing bias and fulfilling personalized precision medicine.

“Equality and minimization of bias in healthcare has recently become prioritized by healthcare systems as recognition of racial bias has come to the forefront in many non-healthcare aspects of society”

“One dose standard protocols and using race as a surrogate for genotype can both potentiate racial disparities in tacrolimus dosing. Routine CYP3A5 genotyping is a more accurate predictor of drug response than race alone and deemphasizes race as a biological variable in clinical care”