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. 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.
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 knowledge base. 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. 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. 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.
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).
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 knowledge base 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 knowledge base. 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
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:
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.
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. VIPs also provide links to summaries for particularly important variants within that gene – these are known as VIP Variant summaries.
… excerpt ends here. Continue reading the full article.
