PharmGKB
PMID 22992668 | |
Release date | 2000 |
---|---|
Access | |
Website | www |
Download URL | www |
Web service URL | api |
Miscellaneous | |
License | Creative Commons BY-SA 4.0 www |
Curation policy | Yes |
The Pharmacogenomics Knowledgebase (PharmGKB) is a publicly available, online knowledge base responsible for the aggregation, curation, integration and dissemination of knowledge regarding the impact of human genetic variation on drug response.[1] It is funded by the National Institutes of Health (NIH) National Institute of General Medical Sciences (NIGMS), and is a partner of the NIH Pharmacogenomics Research Network (PGRN). It has been managed at Stanford University since its inception in 2000.[2]
Purpose
The main goal of PharmGKB is to aid researchers in understanding how variation in a person’s genetic makeup affects how he or she responds to a drug, a field known as
Content
PharmGKB has many different types of PGx-related information available through the website, discussed in the sections below. PharmGKB has PGx content on genetic variants (including
Variant Annotations
Variant annotations are summaries describing how a particular
Clinical Annotations
Clinical annotations combine all variant annotations that discuss the same variant-drug phenotype association and bring them together into a single written summary of the association. Clinical annotations consist of summary text, which is written as the association for each genotype as compared to other genotypes. Below this summary text, clinical annotations contain a list of all the variant annotations that support this particular variant-drug phenotype association. Each clinical annotation is also given a level of evidence, providing a measure of confidence in the association. The level of evidence for a clinical annotation is manually assessed, and is based on criteria such as the number of studies finding positive versus negative results, p-values and study sizes:[1][3][8]
- Level 1A: Clinical annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a Pharmacogenomics Research Network (PGRN) site or in another major health system.
- Level 1B: Clinical annotation for a variant-drug combination where the preponderance of evidence shows an association. The association must be replicated in more than one cohort with significant p-values, and preferably will have a strong effect size.
- Level 2A: Clinical annotation for a variant-drug combination that qualifies for level 2B where the variant is within a Very Important Pharmacogene (VIP) as defined by PharmGKB. The variants in level 2A are in known pharmacogenes, so functional significance is more likely.
- Level 2B: Clinical annotation for a variant-drug combination with moderate evidence of an association. The association must be replicated but there may be some studies that do not show statistical significance, and/or the effect size may be small.
- Level 3: Annotation for a variant-drug combination based on a single significant (not yet replicated) or annotation for a variant-drug combination evaluated in multiple studies but lacking clear evidence of an association.
- Level 4: Annotation based on a case report, non-significant study or in vitro, molecular or functional assay evidence only.[3][9]
Very Important Pharmacogene (VIP) summaries
VIPs are overviews of important genes involved in drug response. They are intended to provide users a better understanding of a particular PGx-relevant gene, and consist of background information on the gene, including any disease associations, and an in-depth review of its
Pathways
PharmGKB pathways are evidence-based diagrams detailing the pharmacokinetics (PK) or pharmacodynamics (PD) of a PGx-relevant drug, accompanied by text providing background on the drug and a discussion of its PK, PD and PGx. Pathways are typically published in the journal Pharmacogenetics and Genomics.[1][8] Pathways are manually created after an extensive literature review, and the connections on the pathway diagrams are supported by literature citations; these supporting citations can be viewed in the online versions of the pathways. Additionally, the information contained within each pathway diagram is available for download in TSV, BioPAX and GPML formats.[1][8]
Dosing guidelines
PharmGKB provides PGx-based drug dosing guidelines from CPIC, as well as The Royal Dutch Association for the Advancement of Pharmacy Pharmacogenetics Working Group (DWPG) and professional societies such as The American College of Rheumatology.[1] More information about the DPWG and their objectives and methods can be found at the PharmGKB website.[11]
CPIC
CPIC consists of members of
FDA and EMA drug labels
PharmGKB curates and annotates drug labels containing PGx information from both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).[1] FDA-approved drug labels with PGx information are sourced from the FDA’s Table of Pharmacogenomic Biomarkers in Drug Labels page, or identified by curators. EMA-approved drug labels (known as European Public Assessment Reports (EPARs)) are manually searched for using the drugs in the FDA Biomarker table. PharmGKB tags each FDA or EMA label with a PGx level based on internally created guidelines:
- Genetic testing required: The label states or implies that some sort of cytogenetic studies, etc., should be conducted before using this drug. This requirement may only be for a particular subset of patients. PharmGKB considers labels that state the variantis an indication for the drug, as implying a test requirement. If the label states a test "should be" performed, this is also interpreted as a requirement.
- Genetic testing recommended: The label states or implies that some sort of cytogeneticstudies, etc., is recommended before using this drug. This recommendation may only be for a particular subset of patients. PharmGKB considers labels that say testing "should be considered" to be recommending testing.
- Actionable PGx: The label does not discuss genetic or other testing for toxicity due to such variants. The label may mention contraindication of the drug in a particular subset of patients but does not require or recommend gene, protein or chromosomaltesting.
- Informative PGx: The label mentions a gene or protein is involved in the metabolism or pharmacodynamics of the drug, but there is no information to suggest that variation in these genes/proteins leads to different response.[15][16]
See also
- pharmacogenetics
- pharmacogenomics
- pharmacokinetics
- pharmacodynamics
- Pharmacogene Variation Consortium
- Clinical Pharmacogenetics Implementation Consortium
References
- ^ a b c d e f g h i "Overview of the PharmGKB". PharmGKB.
- ^ "PharmGKB History". PharmGKB.
- ^ PMID 22992668.
- ^ a b "What is CPIC?". PharmGKB.
- ^ PMID 21270786.
- ^ PMID 24479687.
- ^ "PharmGKB Projects". PharmGKB.
- ^ PMID 22103613.
- ^ "Clinical Annotation Levels of Evidence". PharmGKB.
- ^ "VIPs: Very Important Pharmacogenes". PharmGKB.
- ^ "DPWG: Dutch Pharmacogenetics Working Group".
- ^ "Annotation of CPIC Guideline for allopurinol and HLA-B". PharmGKB.
- ^ "Annotation of CPIC Guideline for simvastatin and SLCO1B1". PharmGKB.
- ISBN 978-0-12-386882-4.
- ^ "Drug Label Information and Legend". PharmGKB.
- ^ "PharmGKB Blog: PharmGKB Drug Labels: Description, Update and New Features". 14 November 2013.