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.

Expansion of pharmacogenetics education agreed as part of lawsuit settlement

Oregon Health & Science University (OHSU) will introduce new educational initiatives on the risks of prescribing the chemotherapy drug capecitabine to patients with DPD deficiency as part of a lawsuit settlement.

The settlement was reached with Joanne McIntyre, whose husband David died as a result of severe capecitabine toxicity. David carried variations in the gene DPYD, which encodes the DPD enzyme. DPD is involved in metabolism of fluoropyrimidine drugs, including capecitabine. Variants in DPYD, such as those that David carried, can inactivate the DPD enzyme, leading to DPD deficiency. Patients with DPD deficiency are unable to properly metabolize capecitabine and other fluoropyrimidines, and are at risk of experiencing severe drug toxicity. In David's case, this toxicity was fatal.

PharmGKB has annotations of several clinical guidelines for capecitabine and DPYD, including those from CPIC and the DPWG. These guidelines uniformly recommend either a dose reduction or selection of an alternative drug in patients with DPD deficiency.

OHSU will hold seminars to educate clinicians on the risks associated with DPD deficiency, how to identify severe capecitabine toxicity in patients and how to administer the antidote. They will also include a module on the topic in their fellowship program and provide a written resource guide to staff in their oncology department. Going forward, patients identified as candidates for capecitabine chemotherapy will be informed of the risks associated with DPD deficiency and, where appropriate, will be offered testing.

We at PharmGKB applaud Joanne's singular dedication to saving patients' lives and OHSU's commitment to implement these changes. Resources on capecitabine pharmacogenomics, including annotations on clinical guidelines for the use of DPYD genotypes in capecitabine prescribing, can be found at the PharmGKB capecitabine drug page.

Update to PharmGKB Pediatric Summaries - BPCA Drugs

The latest round of PharmGKB’s pediatric drug summaries is now live on PharmGKB pediatric. This release includes summaries for 55 drugs, bringing the total summary count to over 180, now including all drugs on the Best Pharmaceuticals for Children Act (BPCA) priority list in addition to all CPIC guideline drugs.

Drugs with new summaries include:

• Alfentanil
• Amiodarone
• Ampicillin
• Azithromycin
• Bosentan
• Cidofovir
• Ciprofloxacin
• Clindamycin
• Clonidine
• Dexmedetomidine
• Digoxin
• Doxycycline
• Furosemide
• Granisetron
• Griseofulvin
• Heparin
• Hydralazine
• Hydrochlorothiazide
• Hydromorphone
• Hydroxycobalamin
• Hydroxyurea
• Isotretinoin
• Labetalol
• Levofloxacin
• Levothyroxine
• Lidocaine
• Lisinopril
• Lithium
• Lorazepam
• Lurasidone
• Meropenem
• Metformin
• Methylprednisolone
• Midazolam
• Molindone
• Nafcillin
• Nicardipine
• Nifedipine
• Nifurtimox
• Olanzapine
• Pentobarbital
• Piperacillin-Tazobactam
• Pralidoxime
• Prednisolone
• Sertraline
• Sildenafil
• Spironolactone
• Terbutaline
• Timolol
• Topiramate
• Tranexamic Acid
• Valganciclovir
• Vancomycin
• Vecuronium

Response to the American Academy of Pediatrics' Statement "Eliminating Race-Based Medicine"

On May 2nd, the American Academy of Pediatrics (AAP) released a pre-published policy statement titled “Eliminating Race-Based Medicine,” noting that race is a “historically derived social construct that has no place as a biologic proxy.” The statement provides necessary and meaningful commentary on “the medical field’s history of inaccurate applications of race correction and adjustment factors” and calls for the overdue elimination of race-based medicine. We at PharmGKB applaud this statement and believe it is important to engage with this call as pharmacogenomics professionals who urge for the implementation of personalized medicine.

Looking forward in research, there is an urgent need to direct research efforts towards underserved populations to address the issues of health disparities. Additionally, clinical implementation of pharmacogenomics needs the development of truly race-agnostic dosing guidelines and algorithms.

The terms ‘race,’ ‘ethnicity,’ and ‘ancestry’ tend to be used interchangeably when discussing a person’s origins. However, there are distinct differences in their meanings. Race and ethnicity are generally accepted to be social and cultural constructs, respectively, and are not typically assigned based on the genetic information of patients. By comparison, ancestry is a biological construct rooted in genetics.

Race or ethnicity are typically disclosed via self-report at the discretion of the patient or visual assignation by a third party (e.g. clinician, healthcare administrator) and, as such, have little grounding in genetics. The assignment of race or ethnicity also brings significant socio-economic implications which are inherent to the use of these constructs. Moreover, it is an inadequate proxy for genetic ancestry that carries additional complications for transracial adoptees and multiracial patients, among others.

PharmGKB notes that the AAP’s recommendation that “professional organizations and medical specialty societies should identify and critically examine organizational policies and practice guidelines that may incorporate race or ethnicity as independent variables or modifying factors” is a relevant and current point of consideration within pharmacogenomics.

In 2018, PharmGKB replaced the Office of Management and Budget Standards (OMB) race and ethnicity categories used in their curation efforts with a biogeographical grouping system [PMID: 30506572]. While PharmGKB serves as a global resource, these OMB groups are US-centric and, as socio-cultural measures of identity, lack the capacity to capture the scale of global human diversity. The use of these biogeographical groups is intended to standardize and to ensure consistency in communications regarding the variability of pharmacogenetic allele frequencies.

Pharmacogenomics, like other areas within genetics, is impacted by the homogeneity of reference genomes. When dosing algorithms and polygenic risk scores are developed primarily in patients of one ancestry (typically European), differences in allele frequencies across populations may prevent these tools from benefiting populations not represented in the reference data. It’s important to recognize that individual medical experiences are shaped by many different factors, including genetic, socio-economic and geographical and that the collective experience of an underrepresented ancestry or ethnic population is likely to be overlooked or diminished by a relative lack of research in these groups. A greater focus on research in underrepresented populations is crucial to understanding how medical experiences can and do vary between communities, and allows us to meet and address a wider variety of medical needs. In terms of implementation of pharmacogenetic guidance, no study population can fully characterize an individual. 

Almost all CPIC guidelines are ancestry-agnostic. However, there is an exception with a complex history worth addressing, as well as a good example of the importance of expanding allele frequency research. Seminal work in warfarin pharmacogenomics focused on testing for CYP2C9*2 and *3, which are found at a frequency of 13% and 7.5% (respectively) in populations of European ancestry, with other alleles present at <1%. In populations of African ancestry, CYP2C9*2 and *3 alleles are instead found at a frequency of around 1-2% - the highest frequency reduced-function variant in this population is *8, and *5, *6, and *11 are also found at around or over 1% frequency (see the CYP2C9 allele frequency table). As such, in studies or implementation where only *2 and *3 were tested for, patients of African ancestry with these other alleles were likely not identified, and instead they were assigned a *1/*1 diplotype. This has resulted in confusing results, patients who unexpectedly required a decreased dose of warfarin, and reduced confidence in the capacity for genotyping to have the desired effect for the patients’ clinical response. Because of this, the CPIC guideline for CYP2C9, CYP4F2, VKORC1, and warfarin chose to stress the importance of testing for these alleles in populations with African ancestry. 

Yet, these alleles are not absent in other populations, and this approach also fails to acknowledge that patients with mixed ancestry may not identify as of African descent and that some patients may not know whether they have African ancestry. The CPIC guideline does provide optional guidance for patients without African ancestry with CYP2C9*5, *6, *8, and/or *11 that is similar to the guidance provided for patients with African ancestry, but only for patients who already have information for these alleles - and does not include recommendations for testing for these alleles in patients without African ancestry.

Currently, these alleles do not have differing effects based on the patient’s ancestry - the distinction is in the frequency, not the clinical implementation. Testing every patient for these alleles would be beneficial, even if only to catch the few patients in other populations and those with multiple or uncertain ancestries who also carry these alleles. It is, after all, called personalized medicine.

The CPIC guideline also refers specifically to the SNP rs12777823 in recommendations for African-American patients only (not all patients of African ancestry). This is the only guideline where it states not to use a genetic result in some individuals - “the data do not suggest an association between rs12777823 genotype and warfarin dose in non-African Americans, thus rs12777823 should not be considered in these individuals (even if available).”

This SNP is found across all populations (according to gnomAD v2.1.1), and has been stated to affect warfarin response in African-American patients [PMID: 26024874] [PMID: 26877068] [PMID: 28686080]. The mechanism by which this SNP affects warfarin response is unknown - the SNP is intergenic, but close to CYP2C18, and is largely assumed to be a marker in linkage disequilibrium (LD) with something else [PMID: 23755828]. While further study is needed, it’s unlikely that this SNP itself has a function in people of one genetic ancestry but not in others, and more likely that the frequency of LD with a mechanistic variant varies by populations. 

This call for race-agnostic pharmacogenetic clinical implementation is not limited to warfarin - several papers have been published discussing the U.S. Food & Drug Administration’s use of race as a limitation in recommendations for pharmacogenetic testing related to carbamazepine and allopurinol [PMID: 18840252] [PMID: 33492362]. This conversation is not a new one - from letters of support arguing against use of race to determine whether it is appropriate to test patients for HLA variants prior to initiating allopurinol therapy [PMID 30383575] to responses validating race-agnostic approaches to HLA genotyping [PMID: 30383576].

In summary, PharmGKB applauds the AAP’s statement calling for the elimination of race-based medicine. It is critical for the field of pharmacogenomics to examine how we can incorporate race-agnostic approaches to PGx implementation while acknowledging the critical importance of research in diverse populations to identify crucial PGx variants. Race-agnostic PGx implementation has the potential to meet a wider variety of individual medical needs, particularly with respect to underrepresented populations and those patients with non-monolithic ancestry, and it continues to be critical from a scientific standpoint to further expand our understanding of allele frequencies beyond Eurocentric frames of reference.

(For those interested in learning more, ClinGen’s Ancestry and Diversity working group, in collaboration with ELSIhub, are currently running a series of conversations on populations descriptors (i.e., race, ethnicity, and ancestry), and several of the speakers have pointed to the distinctions between these terms, particularly with respect to clinical genetics.)

Teri E. Klein (Principal Investigator of PharmGKB, CPIC, PharmCAT, and Stanford ClinGen)
Michelle Whirl-Carrillo (Co-Principal Investigator and Director of PharmGKB)
Li Gong
Rachel Huddart
Ingrid Keseler
Clarissa J. Klein
Binglan Li
Caroline F. Thorn
Matt W. Wright (Director, Stanford ClinGen)
Mark Woon

Ask a Curator for Healthcare Professionals on June 7th

We are holding an Ask a Curator zoom targeted towards healthcare professionals wanting to learn more about PharmGKB and pharmacogenomics. This is part of NHGRI’s Healthcare Professionals Genomics Education Week (#MedGeneEd22). Be sure to spread the word to colleagues who may find this useful.

We are asking people to please register in advance with their questions so curators can better focus these events. There will also be the opportunity to ask questions during the event. Events will be limited to 25 participants to allow enough time for everyone’s questions to be answered.

Sign up here for Tuesday June 7th at 12pm EST, 9am PST, 5pm GMT
Want to be notified about future Ask a Curator events? Join our mailing list here.

What does *1 really mean? And why does that matter?

A Haiku about PGx for National Poetry Month.

Diagnosed star one,

Yet severe toxicity.

What did the lab test?

What does *1 really mean? And why does that matter?

The star alleles of the drug metabolizing enzyme genes are an unusual way of defining variation and are perhaps one of the most misunderstood aspects of pharmacogenomics. Arising from attempts to describe and standardize the molecular basis of different drug phenotypes; debrisoquine poor metabolizer phenotype, etc [PMID: 7773298, PMID: 8807658].  Sometimes authors use the term “wild type”, even for humans, to describe the most common form of the gene or protein in a given population where it displays the expected drug metabolism phenotype. The *1 allele is generally used to denote the absence of the variants tested. However, it is not a stable assignment; a *1/*1 individual only tested at one locus may not have the same genetic sequence as a *1/*1 individual tested for a panel of 10 variants in the same gene. This really matters when evaluating the likelihood of drug phenotype - the "reference" is only as good as the number of variants that were checked. *1 is rather a placeholder, it is the absence of certainty, because even with a panel that covers variants that represent 99% of known variation (in the populations examined so far which are not representative of the full global population) there may still be rare variants with significant impact on protein function that we may not yet have documented. While a *1/*1 may not be at increased risk of toxicity (or other phenotypes), or require a change of dosage immediately, they still have the baseline level of risk and it shouldn’t be a huge surprise if they exhibit an adverse reaction to a drug. 

Recent publications of case studies that concluded a lack of involvement of known pharmacogenes without documenting what was tested: 

PMID:35180762 - “Acral Skin Rash Caused by Altered Mercaptopurine

Metabolism in Maintenance Therapy for B-Cell

Acute Lymphoblastic Leukemia”  excerpt “TPMT and NUDT15 genotype at diagnosis were wildtype alleles and therefore we started with full 6-MP dosing.”

This issue is not limited to pharmacogenes using star allele nomenclature: “5-Fluorouracil Neurotoxicity in the Absence of Dihydropyrimidine Dehydrogenase Deficiency Case Report” [PMID:35419161] excerpt “Our patient tested negative for DPD mutations, but it remains possible she harbored a genetic variant not accounted for in the genetic testing panel. Other known risk factors include mutations in the orotate phosphoribosyltransferase and thymidylate synthase genes… “

We recommend authors always include the list of all variants that were tested, and other features see [PMID:30406943].