The PharmGKB is a pharmacogenomics knowledge resource that encompasses clinical information including dosing guidelines and drug labels, potentially clinically actionable gene-drug associations and genotype-phenotype relationships. PharmGKB collects, curates and disseminates knowledge about the impact of human genetic variation on drug responses through the following activities:
PharmGKB offers information as:
VA Variant Annotations (Research-level annotations of individual publications describing the relationship between genetic variants and drugs; these are created on a paper-by-paper basis)
PW Drug-Centered Pathway
VIP Very Important Pharmacogene Summaries
CA Clinical Annotations (Genotype-based pharmacogenomic relationships summarizing all variant annotations regarding the same genetic variant-drug association)
DG Pharmacogenomics-Based Drug-Dosing Guidelines
DL Drug Labels with Pharmacogenomic Information
Figure 1: The PharmGKB Knowledge Pyramid. A visual representation of the information available at www.pharmgkb.org and the research by the PharmGKB team.
The PharmGKB Knowledge Pyramid (Figure 1) provides users with a visualization of the different types of information found in our knowledge base and, how this information is acquired and integrated together - from the accumulation of gene-drug knowledge at the bottom of the pyramid, to the implementation of pharmacogenomics in the clinic at the top. Each step of the pyramid is described below.
While the terms 'pharmacogenetics' and 'pharmacogenomics' might be technically distinct, they are often used interchangeably and PharmGKB uses 'PGx' to represent both terms throughout the PharmGKB website.
Figure 2: Knowledge Extraction. Gene-drug relationships are extracted from the literature.
The primary pharmacogenomic literature, such as publications found in PubMed and published by researchers and clinicians in the field of pharmacogenetics, forms the base of the PharmGKB knowledge pyramid (Figure 1). From here, the scientific curators read the literature and use Manual Curation to extract gene-drug-disease relationships from the pharmacogenetic literature (Figure 2). Curated pharmacogenetic literature can be found throughout the PharmGKB and provides the foundation for the pyramid.
There is a large volume of pharmacogenetic articles published daily (as demonstrated by the wide base of the pyramid), and we are currently developing Natural Language Processing techniques in order to capture relevant pharmacogenetic text more effectively, allowing our Scientific Curators to then focus on these publications.
Figure 3: Knowledge Annotation, Aggregation and Integration.
Using manual curation, our Scientific Curators add associations between specific genetic variants and drugs reported in the pharmacogenetic literature - these are our Variant Annotations found at the next step of the Pyramid. Our variant annotations report the findings in a single publication using a uniform sentence. These sentences use standardized terminologies, and are integrated into our database enabling them to be easily searched or downloaded, with links to the gene, drug and disease pages. The Variant Annotations can be found throughout the PharmGKB website when you click on the VA icon (VA).
Through extensive literature review, our Scientific Curators also create pathways that are centered around a particular drug that has pharmacogenetic associations. These are either pharmacokinetic (PK) pathways (what the body does to the drug; absorption, distribution, metabolism, elimination) or pharmacodynamic (PD) pathways (what the drug does to the body) (Figure 4). These provide an evidence-based diagram of the genes that interact with a particular drug, a summary of the pathway, and links to related literature, drugs, genes and diseases: PharmGKB Pathways. The PW icon on our website indicates that a pathway is available for a particular drug or gene (PW).
Figure 4: How genetic variants can be involved in the Pharmacokinetic or Pharmacodynamic pathways of a drug.
Our Very Important Pharmacogene (VIP) summaries are written by our Scientific Curators through extensive literature review to provide a concise summary of an important gene involved in drug response. On our website, these provide links to important variants or haplotypes in the gene, relevant drugs, diseases and literature: PharmGKB VIP Summaries. The VIP icon (VIP) on our website indicates that a VIP summary is available for a particular gene, variant or haplotype.
Many of our Pathways and VIP summaries are written in collaboration with experts in the field and are published, and can be found in our PharmGKB Publications list.
Figure 5: Clinical Interpretation.
The fourth layer of the pyramid, Clinical Interpretation, is formed from the information that is available in the PharmGKB through knowledge annotation, aggregation and integration. The PharmGKB Scientific Curators review the Variant Annotations for a particular genetic variant - drug association pair, and aggregate these to write a summary of the association between the drug and each genotype of the genetic variant. These summaries are our Clinical Annotations and are written in a clear standardized format that is understandable to clinicians and researchers. Each Clinical Annotation is given a level of evidence depending on specific criteria, including study size and statistical relevance of the association. Clinical Annotations can move up or down the evidence scale if new variant annotations provide further strength of evidence for the association, if the association becomes implemented in the clinic, or contradictory findings are published. Our criteria can be found at: Clinically relevant PGx summaries. The CA icon on our website indicates that a Clinical Annotation is available for a drug, gene or variant (CA).
Our Variant Annotations provide the drug-variant associations reported in a single publication. Our Clinical Annotations differ from our Variant Annotations in a number of ways, including; 1) Clinical Annotations are an accumulation of the Variant Annotations we have for a particular variant-drug association and therefore they may be based on numerous publications, 2) each variant-drug association is assigned a level of evidence, 3) for each genotype of the genetic variant, a summary is written for the association with the drug, 4) the summaries provide a clinical interpretation for a particular variant-drug association.
Figure 6: Clinical Implementation of pharmacogenetics.
At the top of the PharmGKB Pyramid, supported by the layers below, is the Clinical Implementation of pharmacogenetics. This includes information on our website that is relevant to the clinic, such as FDA drug labels with highlighted pharmacogenetic information (Drug labels with PGx information). The DL icon on our website indicates that a drug label is available for a drug or gene (DL). The PharmGKB is host to several consortia groups who are carrying out pharmacogenetics research to answer important questions, or who are bringing pharmacogenetics into the clinic. The Clinical Pharmacogenetics Implementation Consortium (CPIC) writes drug dosing guidelines based on an individual's genotype. These drug dosing guidelines can be found within our database, along with those published by others (i.e., Dutch Pharmacogenetics Working Group (DPWG)): PGx drug dosing guidelines. The DG icon on our website indicates that a PGx-based dosing guideline is available for a gene or drug (DG).