A Variant Annotation is a summary created for a particular genetic variant associated with a drug described in a single publication. Essential information regarding the pharmacogenetic association is provided, such as the alleles or genotypes described, the phenotypic effect or effect on drug metabolism, study characteristics of the population, and statistics. Variant Annotations summarize the findings of a variety of study types, including clinical trials, clinical case studies, genome-wide association studies, and functional in vivo
and in vitro
studies. Curators also endeavor to cover pharmacogenetic studies mentioned within a review, introduction or discussion. Variant Annotations are represented by the ‘VA’ symbol throughout the PharmGKB website ( & ). Links to PubMed®
IDs (PMIDs) [102
] within pathway descriptions and VIP summaries also link to curated Variant Annotations.
An example of a Variant Annotation in our new standardized format is shown in , for PMID 21383771 [1
]. Below the article title and abstract, the gene, drug and diseases mentioned in the article are displayed. These link directly to the individual gene, drug and disease pages. A symbol is provided to tag whether a pharmacokinetic (PK) or pharmacodynamic (PD) relationship is discussed (). In this example, the journal discusses the genes CYP2C9
and response to the drug warfarin. Although the CYP2C9
genes are involved in the metabolism of warfarin, the annotated article studies responses to warfarin (PD) and not the PK of the drug, and therefore, it has been labeled with a PD tag by the curator.
A Pharmacogenomics Knowledge Base (PharmGKB) Literature Annotation, with Variant Annotations
Individual Variant Annotations for any genetic variants investigated for a drug interaction are provided in the table (). Variant Annotations include those for single nucleotide polymorphisms (SNPs), insertions or deletions (indels), copy number variants and haplotypes. Full haplotype spreadsheets can be downloaded from the ‘Haplotype’ tab of a gene page, if available. For PMID 21383771, three different Variant Annotations with a PD relationship with warfarin are given (). The National Center for Biotechnology (NCBI) SNP database (dbSNP) [103
] reference SNP identification (rsID) is used as a reference for each variant. A standardized sentence is provided, describing the association of the allele or genotype with a drug response. For the CYP2C9
variant rs1057910 “Genotype AA is associated with increased dose of warfarin in people with a stable therapeutic international normalized ratio between two and three as compared to genotypes CC + AC”. This individual association is labeled with a PD relationship, as response to warfarin is discussed in the article. Study parameter details relevant to the significance of the association are collected, including study size, race, allele frequencies and the p-value of the association. For example, the variant associations described in PMID 21383771 were found in a study of 248 Asian individuals, and the association between rs1057910 genotype AA and increased dose of warfarin was statistically significant at p = 0.000161. This information is then stored in our database, and is valuable to both users as well as to curators when compiling Clinical Annotations (see ‘Clinical Annotations’ section below).
Our previous Variant Annotations allowed free text and were subject to the curator’s own approach. The aim of this new feature is to standardize the annotations, provide the most essential information relevant to the pharmacogenetic association, and allow all the information to enter our database so it can easily be searched or downloaded by users. We have integrated internal microdictionaries from which standardized terms can be selected. Disease and phenotype ontologies are sourced from the National Library of Medicine’s Medical Subject Headings (MeSH browser) [104
], and drugs, compound and substance ontology from DrugBank [2
], the WHO’s Anatomical Therapeutic Chemical (ATC) classification system [106
] or PubChem®
]. Unfortunately, the rsID is often not used in the paper, and we urge authors to use this form of identification to standardize genetic variant nomenclature throughout the scientific community in their future published works, facilitating the creation of useful annotations by our curators. If not provided in the article, identifying the rsID for a gene variant can entail several resources including use of PharmGKB Variant Annotations, literature cross-referencing, HapMap [108
], Online Mendelian Inheritance in Man®
] or mapping to the human reference genome sequence, to ensure the correct position and, thus, the correct variant identification is obtained. If a gene or locus is associated with a drug, but no specific variant is mentioned in the article, the publication is curated by adding the relationships into our database as a Literature Annotation, represented by the ‘LA’ symbol (). These can be accessed by a variety of means, by clicking on the LA icon, by searching directly for a publication using the PMID or searching for a drug, gene or disease, and found under the ‘Is Related To’ tab ().