PharmGKB

PharmGKB
Content
Description The Pharmacogenomics Knowledgebase
Data types
captured		 Pharmacogenomics and Pharmacogenetics
Organisms Human
Contact
Research center Stanford University
Primary citation PMID 22992668
Release date 2000
Access
Website www.pharmgkb.org
www.pharmgkb.org/news.jsp
Download URL www.pharmgkb.org/downloads
Miscellaneous
License for non-commercial uses
Curation policy Yes

The Pharmacogenomics Knowledgebase (PharmGKB) is a publicly available, online knowledgebase 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 pharmacogenomics or pharmacogenetics (PGx). In order to achieve this goal, PharmGKB manually curates PGx information from the primary literature, and then stores it in the knowledgebase. This information can be aggregated, allowing PharmGKB to identify consistent genetic variant-drug response interactions. Variant-drug interactions with a large amount of supporting evidence may then be considered for potential clinical implementation.[3] In order to capitalize on cases where strong PGx literature evidence exists, PharmGKB cofounded the Clinical Pharmacogenetic Implementation Consortium (CPIC), an organization responsible for the creation and dissemination of peer-reviewed, freely available genotype-based drug-dosing guidelines for clinicians.[4][5][6] PharmGKB also works with various international consortia groups, such as the International Warfarin Pharmacogenetics Consortium (IWPC) and the International Clopidogrel Pharmacogenomics Consortium (ICPC), facilitating collaboration and analysis of large PGx datasets.[7][8]

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 single-nucleotide polymorphisms (SNPs) and haplotypes, as well as some copy number variations (CNVs) and indels), genes, drugs, phenotypes (including diseases and side effects) and PubMed IDs (PMIDs).[1]

Variant Annotations

Variant annotations are summaries describing how a particular genetic polymophism is associated with a drug response, as reported in a single publication. Examples of drug responses include adverse drug reactions, changes in drug efficacy and alterations in how quickly or slowly a drug is metabolized. Curators review past and present literature and add any studies containing PGx-relevant results to the knowledgebase through these variant annotations. The variant-drug associations may be negative or positive, and they come from a wide variety of study types, including genome-wide association studies, clinical trials, and functional in vitro studies. All variant annotations contain a standardized sentence, which allows results to be easily compared and contrasted between studies throughout the knowledgebase. In addition to recording the genetic variant-drug phenotype association, key study parameters such as study size, population ethnicity, p-values and allele frequencies are also noted in the annotation [1][3][8]

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]

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 pharmacogenetics. Though VIPs are available on the PharmGKB website in an interactive format, they are also typically published in the journal Pharmacogenetics and Genomics.[1][8] VIPs also provide links to summaries for particularly important variants within that gene – these are known as VIP Variant summaries.[10]

List of PharmGKB VIP Summaries.

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]

List of PharmGKB Pathways.

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 page for the group

CPIC

CPIC consists of members of NIH Pharmacogenomics Research Network (PGRN), PharmGKB staff, and experts in PGx and medicine. The goal of CPIC is to create freely-available, peer-reviewed drug-dosing guidelines for clinicians who have access to pre-emptive genetic testing results.[4][5][6] CPIC guidelines are written for PGx associations that have substantial supporting evidence, such as the associations between HLA-B*58:01 and Stevens-Johnson Syndrome/toxic epidermal necrolysis in patients taking allopurinol,[11] and SLCO1B1 rs4149056 and myopathy in patients taking simvastatin[12] CPIC guidelines are published in the journal Clinical Pharmacology & Therapeutics, and are also available through PharmGKB in an interactive format.[6] CPIC dosing guidelines on PharmGKB include an excerpt from the published guideline, the therapeutic dosing recommendations in a table format, and PDF versions of the guideline and supplement. PharmGKB also provides a dosing guideline tool, where users can enter in a genotype of interest and receive the relevant dosing recommendation. Downloadable, computable versions of the guidelines in JSON format are also available on PharmGKB.[13]

List of CPIC Dosing Guidelines

List of all PharmGKB Dosing Guidelines

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:

Several issues exist in the curation of FDA-approved drug labels; these are discussed in a 2013 PharmGKB blog post.

List of FDA and EMA Drug Labels

See also

References

  1. 1 2 3 4 5 6 7 8 9 http://www.pharmgkb.org/page/overview
  2. ↑ http://www.pharmgkb.org/page/history
  3. 1 2 3 4 Whirl-Carrillo M, McDonagh EM, Hebert JM, et al. (October 2012). "Pharmacogenomics knowledge for personalized medicine". Clin Pharmacol Ther. 92 (4): 414–7. doi:10.1038/clpt.2012.96. PMC 3660037Freely accessible. PMID 22992668.
  4. 1 2 http://www.pharmgkb.org/page/cpic
  5. 1 2 Relling MV, Klein TE (March 2011). "CPIC: Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network". Clin Pharmacol Ther. 89 (3): 464–7. doi:10.1038/clpt.2010.279. PMC 3098762Freely accessible. PMID 21270786.
  6. 1 2 3 Caudle KE, Klein TE, Hoffman JM, et al. (February 2014). "Incorporation of pharmacogenomics into routine clinical practice: the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline development process". Curr Drug Metab. 15 (2): 209–17. PMC 3977533Freely accessible. PMID 24479687.
  7. ↑ http://www.pharmgkb.org/page/projects
  8. 1 2 3 4 5 6 McDonagh EM, Whirl-Carrillo M, Garten Y, Altman RB, Klein TE; Whirl-Carrillo; Garten; Altman; Klein (December 2011). "From pharmacogenomic knowledge acquisition to clinical applications: the PharmGKB as a clinical pharmacogenomic biomarker resource". Biomark Med. 5 (6): 795–806. doi:10.2217/bmm.11.94. PMC 3339046Freely accessible. PMID 22103613.
  9. ↑ http://www.pharmgkb.org/page/clinAnnLevels
  10. ↑ http://www.pharmgkb.org
  11. ↑ http://www.pharmgkb.org/guideline/PA166105003
  12. ↑ http://www.pharmgkb.org/guideline/PA166105005
  13. ↑ Barbarino, Julia M.; Whirl-Carrillo, Michelle; Klein, Teri E. (2014). "PharmGKB: The Pharmacogenomics Knowledgebase" in Handbook of Pharmacogenomics and Stratified Medicine. Elsevier. pp. 289–306. ISBN 978-0-12-386882-4.
  14. ↑ http://www.pharmgkb.org/page/drugLabelLegend on PharmGKB
  15. ↑ http://pharmgkb.blogspot.com/2013/11/pharmgkb-drug-labels-description-update.html
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