A recent paper highlights new variants and genes associated with severe fluoropyrimidine-related toxicity in patients who were genotyped as negative for the four DPYD variants the European Medicines Agency recommends testing for.Online ahead of print in the Human Genomics journal is De Mattia et al "The burden of rare variants in DPYS gene is a novel predictor of the risk of developing severe fluoropyrimidine-related toxicity" [PMID: 37946254].
Monday, November 27, 2023
Thursday, November 9, 2023
In collaboration with CPIC, PharmGKB, PharmCAT and PharmVar, the University of Pennsylvania, Penn Center for Precision Medicine will be hosting the ClinPGx 2024: Knowledge, Implementation, Education meeting June 20th and 21st, 2024 in Philadelphia, PA. The meeting will provide educational content to cover all aspects of PGx implementation including knowledgebases, implementation strategies, informatics, use of AI in precision medicine, clinical laboratory insights, and more. Additional details to soon.
Tuesday, September 26, 2023
- Pharmacogenes included ABCG2, CACNA1S, CYP2B6, CYP2C19, CYP2C9, CYP3A5, CYP4F2, DPYD, G6PD, IFNL3, NUDT15, RYR1, SLCO1B1, TPMT, UGT1A1, and VKORC1. CFTR and the CYP2C cluster variant (rs12777823) were also investigated. CYP2D6 alleles that could be determined from VCF, and therefore not including structural variants, were also predicted.
- The five (5) biogeographic groups are Europeans (n = 187,660), Central/South Asians (n = 3,460), East Asians (n = 637), African Americans/Afro-Caribbeans (n = 1,926), and Sub-Saharan Africans (n = 1,235)
- Frequencies of PGx alleles, diplotypes, phenotypes, and/or activity scores, if applicable, were reported for each gene in each biogeographic group.
1. UK Biobank PGx frequencies complemented the CPIC frequency tables.2. This study reported frequencies for a nontrivial number of PGx alleles that are rare or seldom tested, especially in the non-European group.3. There are uncataloged PGx alleles.
Monday, September 25, 2023
Substance abuse disorders are a significant public health cost [PMID: 34453125]. Prescribers have limited choices for pharmaceutical therapies with only three FDA-approved choices for alcohol use disorder and zero for cocaine use disorder. Disulfiram is an FDA-approved treatment for alcohol use disorder which is also used for cocaine use disorder. There are some preliminary studies on the PGx of disulfiram but little replication.
PharmGKB together with Dr Aneysis De Las Mercedes Gonzalez (Stanford University School of Medicine), have published PharmGKB summary: disulfiram pathway in Pharmacogenetics and Genomics, 2023 Sep 21. doi: 10.1097/FPC.0000000000000509. Online ahead of print. PMID: 37728645. It summarizes the candidate genes involved in disulfiram PGx in pharmacokinetics and action in dopaminergic, seratonergic and noradrenergic neurons and highlights the knowledge gaps.
As always interactive versions of the diagrams with underlying linked evidence, are available on PharmGKB:
Friday, August 18, 2023
Please Take This Survey If Your Site Conducts DPYD Genetic Testing Prior to Fluoropyrimidine Chemotherapy
Dan Hertz (DLHertz@med.umich.edu) and the DPYD Implementation Team are collecting information from sites and clinicians in the USA that conduct DPYD genetic testing prior to fluoropyrimidine chemotherapy treatment. If this applies to you, please complete this brief (<5 minutes) survey on behalf of your site before mid-September. This information will be used to develop best practice guidelines for pre-treatment DPYD testing.
Thanks for your participation!
Thursday, July 13, 2023
Wednesday, July 12, 2023
Phenoconversion in the PGx context is a drug-drug interaction that impacts a drug metabolizing phenotype such that it mimics the effects of a metabolizer genotype (see blog from October 2022). Historically much of the discussion on phenoconversion has focused on CYP2D6.
A new paper in Frontiers in Pharmacology investigates the phenoconversion effects of different CYP2C19 inhibitors [PMID:37361233].
Forty donor liver samples were genotyped for CYP2C19 *2, *3 and *17 and the metabolizer phenotypes predicted. Microsomes were assayed with the probe drug s-mephenytoin and then in the presence of strong CYP2C19 inhibitor fluvoxamine, moderate inhibitors omeprazole and voriconazole and weak inhibitor pantoprazole to look at changes in metabolizer status.
Excerpts from paper:
“Our results demonstrate that the outcome of a DDI is dictated by both inhibitor strength and CYP2C19 activity, which is in turn dependent on genotype and non-genetic factors including comorbidities. …
Fluvoxamine, a strong inhibitor of CYP2C19, caused 86% of *1/*17 donors to become phenotypically IM, whereas most of genetically-predicted IMs were converted to a PM phenotype (57%). In accordance with unaltered CYP2C19 activity in patients with gastroesophageal reflux disease taking pantoprazole, weak inhibition by pantoprazole did not induce phenoconversion…
However, the outcomes of DDIs with moderate inhibitors (omeprazole/voriconazole) matched less well to the proposed phenoconversion model by Mostafa et al, which predicted that NMs/IMs convert to a PM phenotype upon moderate inhibition of CYP2C19. In our study, voriconazole, which acts as a moderate CYP2C19 inhibitor, significantly reduced the drug metabolizing capabilities of CYP2C19 by approximately one level (i.e., from a phenotypic NM to a IM). As a result, 40% of the donors (12/30) were converted into IM or PM phenotypes by voriconazole. Though, none of the NMs were converted into PMs, except for one donor who already exhibited impaired CYP2C19 activity in the absence of voriconazole treatment (basal phenoconversion). For omeprazole, phenoconversion into IM or PM phenotypes was even less frequently seen, in only 10% of the donors …
Altogether, our data suggest that CYP2C19 inhibition by moderate inhibitors can result in phenoconversion, but it seems unlikely to result into a PM phenotype for wild-type *1/*1 genotypes.”
There are a number of interesting results and discussion points:
- There is phenoconversion from disease phenotype - namely diabetes.
- The initial concordance for genotype to phenotype with s-mephenytoin was only 40% and the two CYP2C19*17/*17 did not have ultra-rapid UM phenotype (with Vmax in the low normal NM range). The discussion mentions “other (rare) genetic variants within CYP2C19 could also have influenced the mismatch between predicted and observed activities in our study” but it would have been useful to have ruled out *4. The *17/*17 did produce functional mRNA but the *4 is in the start codon and its impact is on translation not transcription [PMID: 9435198].
- There were two *1/*1 outliers with very high UM phenotype that would be interesting to see further genetic analysis of especially given the escitalopram UM CYP2C-haplotype defined by rs2860840T and rs11188059G in [PMID: 33759177].
Overall, this paper shows that while phenoconversion exists for CYP2C19 based on disease status and DDIs, the impact is not a simple downgrading of phenotype (e.g. from IM to PM) that can be applied in a consistent manner across subjects. The authors show that even for strong inhibitors, phenoconversion happens in 40%-86% of subjects with no clear way to predict which subjects would experience phenoconversion and which wouldn’t. More research on how DDIs alter patient-predicted genotype to phenotype is needed to enable better prediction of patient phenotype for PGx drug dosing recommendations.
Monday, June 26, 2023
The ClinGen Pharmacogenomics Working Group (PGxWG)'s anonymous survey will close soon after this Friday, June 30, 2023. Our goal is to gather opinions and feedback regarding the criteria and terminology that should be used to define clinical validity and actionability for pharmacogenes and variants. If you have not yet had the chance to fill it out or pass it along, please do so soon!
Pharmacogenomics expertise is not required - we are also looking for responses across the broader global genetics and medical communities as well (clinicians, pharmacists, labs, genetic counselors, etc.) All responses are appreciated, no matter who you are or where you are in the world. If you’ve previously completed the survey, we appreciate your contribution and there's no need to submit a second response.
The survey can be accessed at: https://stanforduniversity.qualtrics.com/jfe/form/SV_1IdrrPWBXsV2Xt4. We sincerely appreciate your time and participation, and your willingness to help.
Friday, June 9, 2023
At the upcoming PGRN 2023 annual conference in Memphis, Dr. Teri E. Klein, the principle investigator for PharmGKB, ClinGen, CPIC and PharmCAT, will hold a town hall discussion on ClinPGx: a single integrated resource for Pharmacogenomics (PGx). Dr. Klein will discuss the challenge of the separation of pharmacogenomic resources from clinical genomic resources, and present a long-term, conceptual framework for broadly integrating the available PGx resources into a single resource, ClinPGx.
Dr. Klein will also present at the upcoming ClinGen 2023 Summer Workshop Series on June 16 11am PT. Please come join us. We are actively seeking feedback from the PGx and genomics community on the interest and development of ClinPGx to facilitate the incorporation of PGx into standard of care. Zoom link below:
June 16th, 2023, 11am PT/ 2pm ET
Join Zoom Meeting :
Meeting ID: 870 2701 5818
One tap mobile
+16699006833,,87027015818# US (San Jose)
The ClinGen Pharmacogenomics Working Group (PGxWG)'s anonymous survey is OPEN until June 30, 2023. Our goal is to gather opinions and feedback regarding the criteria and terminology that should be used to define clinical validity and actionability for pharmacogenes and variants. Please help disseminate to ALL (clinicians, pharmacists, labs, genetic counselors, etc.). We are looking for BROAD global participations - please send to your friends and colleagues too! If you’ve previously completed the survey, we appreciate your contribution and there's no need to submit a second response.
The survey can be accessed at: https://stanforduniversity.qualtrics.com/jfe/form/SV_1IdrrPWBXsV2Xt4. We sincerely appreciate your time and participation, and your willingness to help.
Wednesday, May 10, 2023
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 firstname.lastname@example.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 email@example.com.
Monday, May 1, 2023
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”
Thursday, April 13, 2023
CPIC Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4 and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants
The CPIC guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4 and HTR2A genotypes and Serotonin Reuptake Inhibitor Antidepressants has been published in the journal Clinical Pharmacology and Therapeutics. This new guideline updates the CPIC guideline for Selective Serotonin Reuptake Inhibitors and CYP2D6 and CYP2C19, and includes additional Serotonin Reuptake Inhibitor Antidepressants and three additional genes, CYP2B6, HTR2A, and SLC6A4.
The guideline gives specific prescribing recommendations for:
- paroxetine, fluvoxamine, venlafaxine, and vortioxetine based on CYP2D6 phenotypes
- escitalopram and citalopram based on CYP2C19 phenotypes
- sertraline based on CYP2C19 and CYP2B6 phenotypes
Clinical recommendations are not provided for serotonin reuptake inhibitor antidepressants based on HTR2A and SLC6A4 genotypes because the current evidence is mixed and/or insufficient to support clinical validity and utility.
For specific recommendations and further details, please refer to the guideline and supplemental materials on the CPIC website. Annotations of the guideline, including an interactive genotype picker tool for the drugs mentioned above, are available on the PharmGKB website.
Monday, April 10, 2023
I am not a mouse.
It’s the reference allele
I am not a mouse.
It's the common variant
In these folks tested.
Saw on minus strand
G is the major allele
In this group tested.
C is the minor
It’s the reference allele
Last year I wrote a haiku to highlight my gripe about authors declaring a patient a *1 but not stating which alleles were tested so not conclusively ruling out the presence of variants. This year I have a series of haiku on another gripe of mine - authors using the term “wild-type” when talking about humans. I’ve been guilty of it in the past but when we know better we do better. The one upside of it is it's a way one can avoid using terms major/minor allele when those might be different in different populations and thus ambiguous, but I think most study participants would not want to be categorized as wild-type, certainly most would not want to be called mutant (unless it comes with some X-men type powers). The terms I would recommend are “reference allele/genotype” (on genome build …) and “comparison allele/genotype”. If using major/minor allele then state explicitly what base that was in the given population, and describe the population, and which strand the allele was measured on (especially for C/G and A/T variants and genes on minus chromosomal strand). We have been seeing problems lately when authors assume the reference allele on the genome build hg38 is the major allele in most populations and that is not always the case. If in doubt give as much information as possible.
Monday, March 20, 2023
The CYP2D6 allele functionality file has been re-evaluated and updated by experts involved in CYP2D6-related CPIC guidelines. CYP2D6 functions are now assigned up to star allele 163.
Monday, March 13, 2023
The ClinGen Pharmacogenomics Working Group (PGxWG) has just launched a second survey to solicit feedback about the criteria and terminology that should be used to define clinical validity and actionability for pharmacogenes and variants from both the PGx community and the wider genetics and medical communities. Please note that this second survey is not independent of the first, and if you’ve taken the previous survey and have significant PGx familiarity or expertise, there is no need to take this iteration, as it would be redundant due to the overlap in questions.
The ClinGen PGxWG is a multi-disciplinary team of researchers and professionals with expertise in pharmacogenomics (PGx), clinical pharmacology, medical genetics, regulatory affairs, and molecular diagnostics. It was launched in February 2022 with the goal of developing a framework of tiered standard terminology and definitions that reflect clinical significance for genes and genomic variants implicated in drug response, in order to facilitate the incorporation of PGx knowledge into ClinGen and more consistent interpretation of PGx variants identified by panel testing and/or sequencing.
The survey is open now and can be accessed at: https://stanforduniversity.qualtrics.com/jfe/form/SV_1IdrrPWBXsV2Xt4. All responses are greatly appreciated, no matter who you are or where you are in the world. Unlike the previous survey, this survey does not assume PGx familiarity, though if you have not taken the previous survey and have PGx familiarity, your feedback is still greatly appreciated. The survey takes approximately 15 minutes to complete. We sincerely appreciate your time and attention, and your willingness to help.
Monday, February 6, 2023
Thursday, January 26, 2023
PharmVar announces several updates for CYP3A4 star allele definitions.
Retirement of the CYP3A4*1G allele: this allele was defined by a common variant in intron 10 (c.1026+12G>A) which was also found on many other haplotypes (or star alleles). PharmVar transiently designated the CYP3A4*1G allele as *36 due to a possible role of c.1025+12G>A being involved in the regulation of CYP3A4 expression. However, owing to the growing body of inconsistent findings regarding associations of c.1026+12G>A and higher or lower expression levels and/or CYP3A4 activity, PharmVar withdrew this redesignation in January 2023 (v5.2.17) which led to the retirement of the CYP3A4*36 (former *1G) allele. Per PharmVar rules, intronic variants are only utilized for star allele definitions if there is convincing evidence that the variant impacts protein function. Therefore, c.1026+12G>A was also removed from all other star allele definitions.
CYP3A4 gene regulation is complex and appears to be governed by a layer of processes, among them long noncoding RNAs, microRNAs and transcription factors which may also influence CYP3A5 activity. Furthermore, there is substrate overlap between CYP3A4 and CYP3A5 and thus, variation in the CYP3A5 gene, further complicates the characterization of CYP3A4 allele function. Investigators are encouraged to include c.1026+12G>A in their carefully designed investigations to produce conclusive evidence regarding the functional impact of c.1026+12G>A.
We would also like to highlight the addition of a novel star allele, CYP3A4*38 which is characterized by two variants which on their own define CYP3A4*3 and *11. Noteworthy, the CYP3A4*3-defining variant c.1334T>C (p.M445T) has also been found together with the intronic SNP defining CYP3A4*22; this allele was designated CYP3A4*37. Consequently, samples heterozygous for these SNPs could have CYP3A4*1/*37 or *3/*22 or *1/*38 or *3/*11 genotypes, respectively. Since the functional impact of c.1334T>C (p.M445T) remains elusive it is unknown whether alternate genotypes differ in function.
Lastly, the evidence level of several alleles has been updated from ‘Limited’ or ‘Moderate’ to ‘Definitive’ indicating that these alleles are now fully characterized.
These efforts were only possible by the dedicated work of the PharmVar Team and the CYP3A4 gene experts for volunteering their time and expertise.
Tuesday, January 24, 2023
CYP4F2 contributes to the synthesis of cholesterol, steroids and other lipids. It has been shown to regulate the bioavailability of vitamin E and vitamin K, a co-factor that is critical to blood clotting. Variations in this important pharmacogene can affect vitamin K levels and thus, the dosing of vitamin K antagonists such as the widely used anticoagulant drug warfarin (CPIC level A and PharmGKB 1A evidence level) among others.
We are excited to announce that CYP4F2 is now fully curated by PharmVar and its gene page content reviewed by an international expert panel. Furthermore, the PharmVar Team has generated new data to provide a more comprehensive catalog of genetic variation of this gene. Not only have the two previously defined CYP4F2*2 and *3 now been fully characterized, several other novel haplotypes (or star alleles) have been identified and designated by PharmVar. Notably, the new and relatively commonly observed CYP4F2*4 allele has both sequence variants that otherwise define *2 (c.34T>G, W12G) and *3(c.1297G>A, V433M), respectively while the other three novel star alleles (CYP4F2*5, *6 and *7) are each characterized by a single amino acid change. Interestingly, CYP4F2*5 and *6 appear to be absent or rare in Asian populations; in contrast, *7 seems to be mostly present in African populations and their descendants. These new star alleles may contribute to unexplained variability in daily warfarin dosage requirements in non-White populations. We encourage the research and clinical communities to include this new knowledge in their investigations.