Nucleic Acids Research Advance Access originally published online on November 21, 2007
Nucleic Acids Research 2008 36(Database issue):D913-D918; doi:10.1093/nar/gkm1009
Nucleic Acids Research, 2008, Vol. 36, Database issue D913-D918
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
The pharmacogenetics and pharmacogenomics knowledge base: accentuating the knowledge
Tina Hernandez-Boussard,
Michelle Whirl-Carrillo,
Joan M. Hebert,
Li Gong,
Ryan Owen,
Mei Gong,
Winston Gor,
Feng Liu,
Chuong Truong,
Ryan Whaley,
Mark Woon,
Tina Zhou,
Russ B. Altman and
Teri E. Klein*
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
*To whom correspondence should be addressed. Tel: +1 650 725 7013; Fax: +1 650 736 0077; Email: teri.klein{at}stanford.edu
Received September 10, 2007. Revised October 24, 2007. Accepted October 24, 2007.
 |
ABSTRACT
|
|---|
PharmGKB is a knowledge base that captures the relationships
between drugs, diseases/phenotypes and genes involved in pharmacokinetics
(PK) and pharmacodynamics (PD). This information includes literature
annotations, primary data sets, PK and PD pathways, and expert-generated
summaries of PK/PD relationships between drugs, diseases/phenotypes
and genes. PharmGKB's website is designed to effectively disseminate
knowledge to meet the needs of our users. PharmGKB currently
has literature annotations documenting the relationship of over
500 drugs, 450 diseases and 600 variant genes. In order to meet
the needs of whole genome studies, PharmGKB has added new functionalities,
including browsing the variant display by chromosome and cytogenetic
locations, allowing the user to view variants not located within
a gene. We have developed new infrastructure for handling whole
genome data, including increased methods for quality control
and tools for comparison across other data sources, such as
dbSNP, JSNP and HapMap data. PharmGKB has also added functionality
to accept, store, display and query high throughput SNP array
data. These changes allow us to capture more structured information
on phenotypes for better cataloging and comparison of data.
PharmGKB is available at
www.pharmgkb.org
|
INTRODUCTION
|
|---|
The Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB;
www.pharmgkb.org) is a public resource that promotes research
into the relationships between human genotypes, phenotypes and
clinical outcomes by linking and annotating primary data sets
from ongoing research and established data from the literature
(
1,
2). In addition to gene–drug relationships, the PharmGKB
also contains data on gene variation, genomics, gene–disease
relationships, drug action and pathways. The PharmGKB has developed
highly curated pathways documenting the genes involved in pharmacodynamics
and pharmacokinetics of a selection of drugs.
We have developed an XML format for defining genotype data, a relational database schema for data storage and a flexible mechanism for submitting phenotype data (3). We are also participating in the PML effort to define an XML standard for genotype/phenotype data exchange. PharmGKB first came online in April 2000, and major updates to the user interface appeared in 2002, 2004 and 2006. PharmGKB data and knowledge are updated on a continuous basis. Access is free but requires users to register for a username and password for viewing individual subject data.
|
DISTINGUISHING PHARMGKB USER GROUPS
|
|---|
PharmGKB supplies a wide variety of pharmacogenomic knowledge
to a broad range of users, from gene-based users to clinical
scientists. In order to better serve our user groups, PharmGKB
has redesigned its website homepage as well as the resource
and submission tabs to more effectively disseminate knowledge
in a form that matches user needs. PharmGKB has identified four
main user groups of the database: gene-oriented users, drug-oriented
users, bioinformaticians and clinical/disease-oriented investigators.
PharmGKB organizes knowledge pertinent to each group into user-based
views and resources.
Figure 1 depicts the PharmGKB homepage
that provides direct links to different user-based knowledge,
such as drug pages or gene pages and more specifically pharmacokinetic
and pharmacodynamic data.
|
INTEGRATING GENOME-SCALE DATA
|
|---|
High-throughput functional genomic technologies have resulted
in the rapid accumulation of genome-scale data sets. There is
a renewed emphasis on genetic variation, partly due to the haplotype
mapping project undertaken by HapMap(
4). The interest lies in
the notion that a single nucleotide polymorphism (SNP) can contribute
directly to disease predisposition by modifying a gene's function,
or that SNPs can be used as genetic markers to tag near neighbor
disease causing mutations through association studies and linkage
analysis. Genetic variation is now measured on a genomic scale
using SNP arrays. The successful analysis of such data sets
depends on rapid access to the most current annotation of the
SNPs being studied in conjunction with phenotypic data, linkage
disequilibrium information and other genomic data (
5). Accordingly,
PharmGKB has added functionality to integrate, aggregate and
annotate data from genome-wide studies. These data can be queried
and viewed by chromosome browsing, gene pages or individual
submission pages.
Figure 2 shows the ABCB1 gene page that has
been populated with an additional 15 variants from an Illumina
317K SNP array, assayed both from traditional and high-throughput
methods.
View larger version (39K):
[in this window]
[in a new window]
[Download PowerPoint slide]
|
Figure 2. PharmGKB VariantPage. CYP2D6 variant page contains information on the variants within the gene boundaries. SNP array data are integrated with traditional PharmGKB primary data and other external variant data, such as dbSNP and JSNP.
|
|
|
VIP GENE AND VARIANT PAGES
|
|---|
Very Important Pharmacogenes, provide annotated information
about genes, variants, haplotypes and splice variants of particular
relevance for pharmacogenetics and pharmacogenomics. VIP gene
pages highlight the key variants, haplotypes, drugs, diseases
and phenotypes associated with the pharmacogene (
Figure 3).
A VIP gene is defined as a gene that has well-documented information
about its involvement in the pharmacodynamics or pharmacokinetics
of a drug. There are a total of about 200 well-documented VIP
genes that were selected by pharmacogenomics experts for PharmGKB
to annotate. VIP pages are hand-curated and contain information
about the mapping of the variant to allow cross comparison with
other resources, frequencies and drug and disease associations
from key studies and the links to the literature that document
them. VIP variants link from the variant page via a flag in
the row for that golden path position.
View larger version (57K):
[in this window]
[in a new window]
[Download PowerPoint slide]
|
Figure 3. PharmGKB very important pharmacogenomic (VIP) genes: PharmGKB gathers knowledge on key pharmacogenomic genes, which highlight important variants, haplotypes, drugs, diseases and phenotypes associated with the gene.
|
|
|
PHARMGKB PATHWAYS
|
|---|
Historically, many pharmacogenetic studies have focused on single
genes involved in drug side-effects. There is now a growing
interest in how pathways of interacting genes can affect both
drug metabolism and drug response. PharmGKB pathways are drug-centered,
depicting candidate genes for pharmacogenetics and pharmacogenomics
studies and they provide the means to connect separate data
sets to represent the current knowledge as a cohesive snapshot.
Pathways are created based on community interest and involvement/contributions.
The diagrams have information content in the shape and color
of the icons that represent whether the component is a gene,
drug, metabolic intermediate, etc. (
Figure 4). The pathways
are interactive: clicking on a gene takes the user to the gene
page from which available genotype and phenotype data and literature
citations can be found. Drugs and metabolites are represented
by rectangles. Clicking on a drug takes the user to the drug
page from which available phenotype data and literature citations
can be found. Clicking on a golden arrow presents the user with
phenotype data that support a relationship. In addition to the
pathway diagram, a summary is provided to describe the content
of the graphic. The pathways are generated by collaboration
of investigators and represent a consensus of the opinions of
the authors. Currently, these pathways are constructed by hand
as graphic images and updated by the scientific community every
2 years. Dates of pathway release and updates are posted on
the pathway pages.
|
LITERATURE ANNOTATIONS
|
|---|
PharmGKB has a collection of pharmaco-related literature annotations
that are generated and enhanced through hand-curation. We allow
reference addition to PharmGKB either as a Publication entry
or as a Literature Annotation, which includes additional hand-curated
details about the reference and the pharmacogenomic relationships
described in the article. To aid users, PharmGKB knowledge generation
is achieved by combining highly searchable controlled vocabulary
classifications of references with brief, detailed free-text
descriptions of the primary research findings. This provides
users with the most flexible access to the knowledge we generate
about the references, depending on their different needs and
preferences.
|
PHENOTYPE DATA SETS
|
|---|
PharmGKB houses a variety of phenotype data sets. All phenotype
submissions are accepted and PharmGKB has expanded submission
methods to include Microsoft Office documents, or alternatively,
a URL to another established archival public database (e.g.
GEO). High-impact phenotype data sets are curated by hand, while
others receive minimal oversight at PharmGKB. High-impact phenotype
data sets correspond to genotype data submitted to PharmGKB
and are typically published in peer-review journals. These data
are featured on the PharmGKB website with an interactive display,
curated annotations and downloadable Excel files. All phenotype
files on PharmGKB are fully text-searchable. PharmGKB also offers
links to web sites with controlled vocabularies in order to
encourage investigators to optimize documentation of their deposits.
The phenotype data set knowledge is available to the general public via an integrated tab-display (Figure 5). For all data sets in PharmGKB, genes, drugs, diseases and categories of pharmacogenetic evidence are tagged and indexed for querying. Curated phenotype data sets are reviewed and include meaningful phenotypic annotations related to pharmacogenomic research, from clinical-metabolite data to protein constructs. Genotype and/or phenotype data can be downloaded by clicking on arrows in the upper right corner of the webpage.
View larger version (42K):
[in this window]
[in a new window]
[Download PowerPoint slide]
|
Figure 5. PharmGKB phenotype data set. PharmGKB displays phenotype data. In the figure, there are five tabs: (i) Overview presents key indexing terms and a summary of the file, (ii) Publications points to key publication summaries, (iii) Column Headers defines the data present in the file and (iv) Individualized Data provides a data browser to look at the primary data. (v) External Data Links point to external data sources relevant to the data set, such as exon arrays stored in other databases.
|
|
|
FUTURE DIRECTIONS
|
|---|
PharmGKB catalyzes the generation of new knowledge in pharmacogenomics
through the development, implementation and dissemination of
a public resource focused on both data and knowledge. In the
short-term, this resource will facilitate basic research. In
the long-term, it will impact how medicine is delivered. Our
future work focuses on detailed annotation of individual human
polymorphisms (or haplotypes) that are important for drug response
phenotypes. We also are active in creating consortia of investigators
interested in pooling pharmacogenomic data sets in order to
improve population coverage and statistical power.
|
ACKNOWLEDGEMENTS
|
|---|
PharmGKB is supported by NIH/NIGMS Grant no. UO1GM61374. Funding
to pay the Open Access publication charges for this article
was provided by NIH/NIGMS grant no. UO1GM61374.
Conflict of interest statement. None declared.
|
REFERENCES
|
|---|
- Thorn CF, Klein TE, Altman RB. PharmGKB: the pharmacogenetics and pharmacogenomics knowledge base. Methods Mol. Biol. (2005) 311:179–191.[Medline]
- Hewett M, Oliver DE, Rubin DL, Easton KL, Stuart JM, Altman RB, Klein TE. PharmGKB: the pharmacogenetics knowledge base. Nucleic Acids Res. (2002) 30:163–165.[Abstract/Free Full Text]
- Whirl-Carrillo MMW, Thorn CF, Klein TE, Altman RB. The PharmGKB XML Schema: an interchange format for genotype-phenotype databases. Human Mutation. (2007) In press.
- Consortium IH. A haplotype map of the Human genome. Nature (2005) 437:1299–1320.[CrossRef][Medline]
- Hernandez-Boussard T, Klein TE, Altman RB. Pharmacogenomics: the relevance of emerging genotyping technologies. MLO Med. Lab. Obs. (2006) 38, 24:26–30.
CiteULike 
Connotea 
Del.icio.us What's this?
TOP
DISTINGUISHING PHARMGKB USER...
INTEGRATING GENOME-SCALE DATA
