Highlighting the relationship between genes, diseases, and drugs is integral to the mission of the PharmGKB. As high-throughput DNA microarray and sequencing technologies continue to improve and become more available, researchers have access to rapidly growing amounts of genotype and phenotype data. The “Variants” feature of the PharmGKB showcases information on genetic variants and presents publication-supported relationships between specific variants and associated phenotypes. Variant information is organized for both ease of use and maximum information content. The PharmGKB currently contains over 370 variant annotations in 176 genes. These numbers are increasing rapidly as PharmGKB curators continue to create new variant entries.
There are several access points to the “Variants” feature. One can click on the “variants of interest” icon found on the PharmGKB homepage to browse through a list of genes for which there exist annotated variants, or one can search for variants in a particular gene by entering that gene’s name in the “Search PharmGKB” box. Entering a dbSNP rsID as a search term will also take the user to the gene in which that variant is located.
depicts a typical Variants page. In this example, variants in the ABCB1 gene are graphically represented in a UCSC Genome Browser–like format. Tick marks designating the locations of SNPs submitted as genotyping data to the PharmGKB are displayed on the PharmGKB labeled track. The height of each tick mark reflects the frequency of that variant. Introns, exons, untranslated regions, promoters, and flanking regions are color-coded to facilitate visualization of these features. The Golden Path track shows the location of gene exons from the UCSC Genome Browser assembly (Karolchik et al., 2008
; Kent et al., 2002
). SNPs found on a custom Illumina 317 SNP array microchip are indicated on the PharmGKB Illumina track (Hernandez-Boussard et al., 2008
). Finally, SNPs in this region from the dbSNP and JSNP databases are represented on the dbSNP (Sherry et al., 2001
) and JSNP (Hirakawa et al., 2002
) tracks, respectively.
Importantly, the Variants display table located beneath the graphical SNP distribution image includes the Golden Path position of each variant to unambiguously pinpoint its location in the human genome relative to a reference sequence and, if known, the dbSNP rsID is listed. This standardized, precise localization of variants eliminates uncertainty in variant position that is sometimes encountered when various variant notations are employed. Additionally, the nucleotides observed at each variant location are listed, and the genomic context of each variant is indicated (e.g., exon, intron, etc.), as well as the amino acids found in variant codons. By clicking on a variant’s Golden Path position, dbSNP rsID, or polymorphic nucleotide, the user is routed to the UCSC Genome Browser, to dbSNP, or to the PharmGKB allele frequency information for that variant, respectively.
The PharmGKB has recently introduced a feature to highlight variants with phenotypic consequences. Variants with an entry in the “Variant of Interest Curation Level” column are supplemented with phenotype information from the literature and from data submissions to the PharmGKB. Three-star (***) annotations indicate in-depth variant curation, with a phenotype summary, literature references, and allele frequency data. Clicking on the “view” link adjacent to the “***” symbol brings up the three-star variant’s “Annotations” tab. One can then access detailed variant information by clicking on the URL provided. This information is the same “Important Variants Information” included in the VIP feature discussed above. Two-star (**) annotations reflect shorter phenotype summaries with accompanying literature references. To access variant annotation content, one can either click on the “view” link, or simply position the mouse pointer over the “view” link to display the variant phenotype summary. One-star (*) annotations are used for those that are generated by computer programs and have not been reviewed by curators.
The PharmGKB Variant Browser serves users in multiple ways. Variants are easy to locate in a gene, and the nucleotides observed at the polymorphic position by data submitters—as well as the amino acids encoded by polymorphic codons—are readily identifiable. This data, used in conjunction with the two- and three-star variant annotations, can serve as the basis for selecting variants to genotype in pharmacogenetics and pharmacogenomics studies.