Tuesday, September 8, 2020

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

The 2020 CPIC Guideline update for HLA-BCYP2C19 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.

Wednesday, August 26, 2020

PharmGKB and CPIC Partner with ClinGen

PharmGKB and CPIC have formalized a partnership with ClinGen to bring pharmacogenomics (PGx) expertise to the primarily disease-focused, NIH-funded mega-resource.  ClinGen's goals include defining the clinical relevance of genes and variants for use in precision medicine and research and disseminating that knowledge to the broader community.  They have developed and implemented data standards for clinical annotation and interpretation of genes and variants. To date, this annotation and interpretation has focused on disease-related genes and variants. The partnership with PharmGKB and CPIC was established to bring PGx knowledge to the ClinGen community.  Gene-level PGx entries which link to PharmGKB and CPIC will be added to the current validation, dosage and actionability curations displayed on ClinGen so that users will be able to access the PharmGKB and CPIC resources through the ClinGen interface.  Planning is underway for the PGx display. Additionally, PharmGKB is working to provide links back to ClinGen for genes and variants associated with disease phenotypes.

Tuesday, August 11, 2020

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 omeprazolelansoprazolepantoprazoledexlansoprazole, 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 omeprazolelansoprazolepantoprazoledexlansoprazole 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.

Monday, August 10, 2020

CYP3A5 released on PharmVar

PharmVar and PharmGKB are excited to announce that CYP3A5 has been transitioned into the PharmVar database. Variation information has been extensively curated by the PharmVar CYP3A5 gene experts which led to the correction of some allele definitions or reclassification of others. The submission of new data added novel suballeles, as well as helped to raise the evidence levels for several alleles from ‘Lim’ to ‘Def’. Important CYP3A5 information is provided in the ‘Read Me’ document such as reference sequences used and how the PharmVar CAVE tool facilitates comparisons of core allele definitions. All changes and revisions have been summarized in the ‘Change Log’ document. Here we also list all new haplotypes. Check it out at https://www.pharmvar.org/gene/CYP3A5.

And finally, a big thank you to all of the CYP3A5 gene experts who serve on this panel for their hard work.

Thursday, July 30, 2020

PharmVar user survey released

The Pharmacogene Variation (PharmVar) Consortium, a central repository for pharmacogene (PGx) variation that focuses on haplotype structure and allelic variation is interested in hearing from the PGx user community regarding their resource.  Please take a couple of minutes to fill out their user survey.

Friday, July 10, 2020

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

Monday, July 6, 2020

PharmVar GeneFocus paper for CYP2C19 is published

The PharmVar GeneFocus: CYP2C19 paper, the second of the GeneFocus series, has just been published by Clinical Pharmacology & Therapeutics.
PharmVar thanks all CYP2C19 experts as well as the PharmGKB team who have served on this panel and diligently curated this gene and reviewed submissions ever since PharmVar was launched back in 2017. This review provides a general overview of CYP2C19 as well as a deeper dive into the nomenclature.
The GeneFocus also provides a summary of a revision of CYP2C19*1. This revision was introduced to apply PharmVar allele definition criteria consistently across all CYP2C19 haplotypes, as well as to align definitions with the current reference sequence and its recently released LRG. Highlights of the revision include:
·       All but one *1 suballele contained g.80161A>G (I331V), which posed a conflict as this SNP is also present on many other star alleles 
·       To resolve this conflict, *1.001 (previously known as *1A) was revised to *38
o   This haplotype matches the NG_008384.3 RefSeq and LRG_584; therefore, there are no SNVs in the *38 core allele definition
o   All remaining *1 subvariants now contain g.80161A>G (I331V); consequently, g.80161A>G (I331V) has been added to the *1 core allele definition
·       *1 subvariants (with g.80161A>G (I331V)) are more commonly observed than *38
o   Commonly used genotyping platforms do not test for g.80161A>G (I331V) and thus, *1 will be assigned by default
·       The I331V amino acid change does not appear to impact function; therefore, both *1 and *38 are normal function
Changes such as the update from CYP2C19*1.001 to *38 may be viewed as ‘interruptive’. However, having standardized nomenclature that is consistently applied will greatly benefit the research and clinical PGx communities moving forward. The revision can now be found on the PharmVar page for CYP2C19.