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

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.

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.

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.

CPIC® Guideline for Potent Volatile Anesthetic Agents and Succinylcholine and RYR1 and CACNA1S update

The ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel recently published recommendations for RYR1 pathogenicity classifications in malignant hyperthermia susceptibility (PMID: 33767344). These revised ACMG/AMP criteria were applied to the 44 variants originally included in the CPIC recommendations (PMID: 30499100) and 29 variants were classified as pathogenic, 13 as likely pathogenic, and 2 as variants of uncertain significance. Based on this classification, the assignment for the variants c.1589G>A p.(Arg530His) and c.1598G>A p.(Arg533His) has been changed from “malignant hyperthermia-associated” to “uncertain function” in the RYR1 allele functionality table.

Information about the update has been added to the CPIC RYR1, CACNA1S and Volatile anesthetic agents and Succinylcholine guideline page and the PharmGKB annotation for this guideline.

PharmGKB Tutorial Published

We are pleased to announce that an updated PharmGKB tutorial has now been published in Current Protocols.

The paper describes how to navigate the PharmGKB website to retrieve information on how genes and genetic variations affect drug efficacy and toxicity. It also includes a protocol on how to use PharmGKB to facilitate interpretation of findings for a specific pharmacogenomic variant genotype or metabolizer phenotype. 

Further information about how to use PharmGKB, including a short guided page tour and training exercises, can be found on our website.

White paper on assigning LOE to clinical annotations now published

A previous blog post described our new quantitative system for assigning a level of evidence (LOE) to clinical annotations. We are pleased to announce that our white paper about the system has now been published in Clinical Pharmacology and Therapeutics and is available on the PharmGKB website.

The paper details how each piece of evidence linked to a clinical annotation is scored by an algorithm and how the total score of a clinical annotation is translated into a LOE. Use of this system makes the assignment of LOE to be more consistent across clinical annotations and allows users to better understand why a certain LOE has been assigned to a particular clinical annotation.

Further information about scoring of variant annotations and clinical annotations as well as our LOE system can be found on our website.

Review and Consensus on Pharmacogenomic Testing in Psychiatry published in Pharmacopsychiatry

Review and Consensus on Pharmacogenomic (PGx) Testing in Psychiatry was recently published in the journal Pharmacopsychiatry [PMID: 33147643].

In the sections pharmacogenomic mechanisms, pharmacogenomic evidence and guidelines for psychiatry, and pharmacogenomic testing in psychiatry the review provides an up-to-date summary of recent developments that clinicians should know when considering PGx testing for their patients. It summarizes and discusses the evidence that was considered by the International Society of Psychiatric Genetics (ISPG) for a statement about “Genetic testing and psychiatric disorders” updated in 2019.

The author group concludes that PGx testing should be viewed as part of the decision supporting measures to assist implementation of good clinical care, highlighting CYP2D6, CYP2C19, HLA-A, and HLA-B. For further details read the review [PMID: 33147643].

PharmGKB tutorial for pharmacogenomics of drugs potentially used in the context of COVID-19

The PharmGKB tutorial for pharmacogenomics of drugs potentially used in the context of COVID-19 is now published in Clinical Pharmacology and Therapeutics.

The article is the first in a series of Pharmacogenomics Knowledgebase (PharmGKB) tutorials intended as a resource to help users become quickly acquainted with the wealth of information stored in PharmGKB. 

Each article will center around a specific topic, like in this publication the PharmGKB COVID-19 portal (previously blogged about it here). 

Using examples of drugs found in the portal the authors demonstrate some of the main features of PharmGKB including guideline, drug label, clinical, and variant annotations.

CPIC Guideline update: HLA-B/CYP2C9 and Phenytoin/Fosphenytoin

The 2020 CPIC Guideline update for HLA-B, CYP2C19 and phenytoin dosing is now published in Clinical Pharmacology and Therapeutics. The accepted article can be accessed on the PharmGKB page for phenytoin and on the CPIC website. 

Phenytoin is an antiepileptic drug with inter-individual pharmacokinetic variability, partly due to CYP2C9 genetic variation, and  a narrow therapeutic index. The presence of the HLA-B*15:02 variant allele is associated with an increased risk of phenytoin-induced cutaneous adverse reactions of Stevens-Johnson syndrome and toxic epidermal necrolysis. 

Literature published after the 2014 guideline was reviewed and the recommendations and supplemental information were updated. This includes updates to CYP2C9 allele assignments using the activity score (AS) system. The CYP2C9*2/*2 diplotype (AS=1) is now translated into the IM phenotype group (originally translated to PM). This is based on similar effects of CYP2C9*1/*3 (AS=1) and CYP2C9*2/*2 on metabolic ratio and dose requirements for multiple substrates. CYP2C9*3 is classified as ‘no function’ allele with an activity value of 0 for AS calculation.

For therapeutic recommendations and further details including an algorithm for suggested clinical actions based on HLA-B*15:02 and CYP2C9 genotype, please refer to the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C9 and HLA-B Genotypes and Phenytoin Dosing: 2020 Update.

New CPIC Guideline: CYP2C19 and Proton Pump Inhibitors (PPIs)

The CPIC Guideline for CYP2C19 and proton pump inhibitor (PPI) dosing is now published in Clinical Pharmacology and Therapeutics. The accepted article can be accessed on the PharmGKB page for omeprazole, lansoprazole, pantoprazole, dexlansoprazole, and on the CPIC website. 

PPIs inhibit the final pathway of acid production, which leads to inhibition of gastric acid secretion. PPIs are widely used in the treatment and prevention of many conditions including gastroesophageal reflux disease, gastric and duodenal ulcers, erosive esophagitis, H. pylori infection, and pathological hypersecretory conditions. The first-generation inhibitors omeprazole, lansoprazole and pantoprazole are extensively metabolized by the cytochrome P450 isoform CYP2C19 and to a lesser extent by CYP3A4. The second-generation PPI dexlansoprazole appears to share a similar metabolic pathway to lansoprazole. CYP2C19 genotypes have been linked to PPI exposure and in turn to PPI efficacy and adverse effects.

The CPIC guideline summarizes evidence from the literature and provides therapeutic recommendations for omeprazole, lansoprazole, pantoprazole, dexlansoprazole based on CYP2C19 genotype. For therapeutic recommendations and further details, please refer to the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C19 and Proton Pump Inhibitor Dosing.

ICPC publishes GWAS analysis on platelet reactivity and cardiovascular response in patients treated with clopidogrel

The GWAS analysis on platelet reactivity and cardiovascular outcome for clopidogrel, the third paper by the International Clopidogrel Pharmacogenomics Consortium (ICPC), has just been published in journal Clinical Pharmacology & Therapeutics.

Clopidogrel is an antiplatelet agent widely used in patients with acute coronary syndrome, percutaneous coronary intervention, or ischemic stroke. Individual responses to clopidogrel show substantial variability, and poor response is often associated with adverse cardiovascular outcomes. Genetic variants in CYP2C19 play an important role in response to clopidogrel. However, loss of function variants in CYP2C19 only account for a small percentage of the overall variation in platelet reactivity, suggesting that novel genetic variants for clopidogrel response remain to be discovered.

The International Clopidogrel Pharmacogenomics Consortium (ICPC) was established to identify genetic factors influencing clopidogrel efficacy and cardiovascular outcomes, using both genome-wide and candidate gene approaches. It comprises 17 study sites from 13 countries that contributed clinical and genetic data for a total of 8,929 patients treated with clopidogrel. Investigators from ICPC performed a GWAS on data from 2,750 individuals of European ancestry. The GWAS analysis showed that CYP2C19*2 is still the strongest genetic determinant of on-clopidogrel platelet reactivity, and no SNP reached genome wide significance for major adverse cardiovascular events (MACE) endpoints. However, in subgroup analyses for patients with coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome, mutations in SCOS5P1, CDC42BPA and CTRAC1 showed genome-wide significance with MACE or stent thrombosis outcomes. This study represents the largest GWAS performed to date for clopidogrel response.

In addition to the GWAS analysis, the ICPC previously published the design paper and results from the candidate gene study, which developed a pharmacogenomic polygenic response score (PgxRS) - based on 31 candidate gene polymorphisms and assessed in 3,391 clopidogrel treated patients from the ICPC.  Several variants in CYP2C19, CES1, CYP2C9, CYP2B6 and PEAR1 were identified to have significantly influenced on-clopidogrel platelet reactivity. Patients who carried increasing number of risk alleles that lead to high platelet reactivity were significantly more likely to experience adverse cardiovascular events than patients who carried alleles that lead to better platelet inhibition.

For more information, please refer to the following publications by ICPC:

1. Genome-wide association study of platelet reactivity and cardiovascular response in patients treated with clopidogrel: a study by the International Clopidogrel Pharmacogenomics Consortium (ICPC). Clin Pharmacol Ther. 2020 May 30. doi: 10.1002/cpt.1911. PMID: 32472697
2. Pharmacogenomic Polygenic Response Score Predicts Ischemic Events and Cardiovascular Mortality in Clopidogrel-Treated Patients. Eur Heart J Cardiovasc Pharmacother. 2019 Sep 3:pvz045. doi:10.1093/ehjcvp/pvz045. PMID: 31504375.
3. Genome-wide and candidate gene approaches of clopidogrel efficacy using pharmacodynamic and clinical end points-Rationale and design of the International Clopidogrel Pharmacogenomics Consortium (ICPC). Am Heart J. 2018 Apr;198:152-159. doi: 10.1016/j.ahj.2017.12.010. PMID: 29653637

New CPIC Guideline: CYP2C9 and Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

The CPIC Guideline for CYP2C9 and Nonsteroidal Anti-inflammatory Drugs (NSAIDs) is now published in Clinical Pharmacology and Therapeutics. The accepted article can be accessed on the PharmGKB pages for a number of NSAIDs drugs, CYP2C9, and on the CPIC website.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs) are among the most commonly prescribed drugs to treat pain and inflammation. The main therapeutic effect of NSAIDs occurs via inhibition of prostaglandin biosynthesis mediated by the cyclooxygenases (COXs). Most NSAIDs are reversible inhibitors of both the COX-1 and COX-2 isoforms. Celecoxib, meloxicam, and diclofenac are selective inhibitors of COX-2. Hepatic metabolism by cytochrome P450 isoforms CYP2C9, 1A2, and 3A4, and renal excretion are the principal routes of clearance of the majority of NSAIDs.  Genetic variants in CYP2C9 (eg. CYP2C9*2 and *3), along with other genetics and clinical factors, have been shown to affect systemic plasma concentrations of NSAIDs and potentially safety. Patients with CYP2C9 decreased or no function alleles may have elevated exposure and at increased risk for adverse effects. 

The CPIC guideline summarizes evidence from the literature and provides therapeutic recommendations for a number of NSAIDs (celecoxib, flurbiprofen, ibuprofen, lornoxicam, meloxicam, piroxicam and tenoxicam) based on CYP2C9 genotype.    For therapeutic recommendations and further details, please refer to the CPIC Guideline for CYP2C9 and Nonsteroidal Anti-inflammatory Drugs (NSAIDs).

Lamotrigine pathway published in Pharmacogenetics and Genomics

The PharmGKB lamotrigine pathway has been recently published in the journal Pharmacogenetics and Genomics.

The publication, written by Taraswi Mitra-Ghosh, now at Auburn University, and Samuel Callisto of the Univeristy of Minnesota along with collaborators, including former PharmGKB Scientific Curator Julia Barbarino, reviews both the pharmacokinetics and pharmacodynamics of lamotrigine. Lamotrigine is an antiseizure drug which has also been approved for the treatment of bipolar disorder. It is extensively metabolized in the liver primarily by UGT enzymes. Although the exact pharmacodynamic effects of lamotrigine remain unclear, it is thought that it may act as an antagonist of voltage-gated sodium channels and voltage-gated calcium channels.

Adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients treated with lamotrigine. A number of alleles at the HLA locus which have been linked to lamotrigine-related adverse events are also reviewed in this paper.

The pathway, including a clickable image, is also freely available on the PharmGKB website.

PharmGKB papers in the February 2020 issue of Pharmacogenetics and Genomics

The February 2020 issue of Pharmacogenetics and Genomics has a PharmGKB double feature, with the publication of our sertraline pathway and our VIP summary for CACNA1S.

The sertraline pharmacokinetic pathway, written by Scientific Curator Dr. Rachel Huddart and collaborators, is featured on the cover of the journal. Sertraline is a selective serotonin reuptake inhibitor (SSRI), which is used in the treatment of some psychiatric disorders, such as major depressive disorder. Metabolism of sertraline in the liver by CYP2C19 forms the basis of clinical guidelines from CPIC and the DPWG.

CACNA1S is a subunit of the dihydropyridine receptor and is expressed in skeletal muscle, where it plays a role in muscle contraction. Variants in CACNA1S have been linked to a number of myopathies as well as malignant hyperthermia, which can occur in some patients when exposed to inhaled anesthetics. The recent CPIC guideline forinhaled anesthetics includes recommendations based on CACNA1S variants. Our VIP summary, written by Senior Scientific Curator Dr. Katrin Sangkuhl with Dr.Robert Dirksen of the University of Rochester and former PharmGKB curator Maria Alvarellos, outlines the role of CACNA1S in both normal muscle function and in disease genetics. Key variants which have been associated with malignant hyperthermia are discussed in detail.

Both the sertraline pathway and CACNA1S VIP summary can be accessed on the PharmGKB website.

Call for clarification on antidepressant pharmacogenomics

A new Perspective in Clinical Pharmacology and Therapeutics outlines the need for improved communication from pharmacogenomic testing companies and regulators on the role of pharmacogenomics in antidepressant therapy.

Beginning antidepressant treatment can be an arduous experience for patients. Some patients fail to respond to first-line antidepressants, leading to an iterative process of trying different medications until depressive symptoms improve, while others experience antidepressant-induced adverse effects. This current situation highlights the need to make evidence-based improvements to the drug selection and dosing process.

Some pharmacogenomic information is included on the US Food and Drug Administration (FDA)-approved labels of a number of antidepressants. However, the actionability of this information can vary widely between labels and there is no guidance to clinicians on when to seek pharmacogenomic testing for a patient. PharmGKB assigns a PGx Level and tags to our drug label annotations to help users easily recognize labels containing actionable pharmacogenomic information such as recommendations for dose or altered drugs.

The publication’s authors, including Dr. Teri Klein and Dr. Katrin Sangkuhl (PharmGKB and CPIC), Dr. Andrea Gaedigk (PharmVar), as well as Dr. Kelly Caudle and Dr. Roseann Gammal (CPIC), argue that the inconsistencies in drug labels combined with the FDA’s recent communications on the safety and validity of pharmacogenomic testing has created confusion among clinicians and patients about pharmacogenomics in antidepressant prescribing. They also highlight the work of CPIC in producing evidence-based clinical guidelines that can be used to guide drug selection and dosing. In particular, the CPIC guidelines for selective serotonin reuptake inhibitors and tricyclic antidepressants are based on the critical review of decades of scientific evidence.

The article ends with a call for clarity on the level of evidence required to implement pharmacogenomic-guided prescribing in the clinic, particularly with reference to sertraline and escitalopram.