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PharmGKB Pharmacogenomics Knowledge Base Tutorial

The PharmGKB Pharmacogenomics Knowledge Base (http://www.pharmgkb.org) is an online resource to learn about drugs, specifically how drugs interact with our bodies on a molecular level, the involvement of genetics in this process, and much more. It was created for the scientific community, but with a little effort and this guide anyone with a basic understanding of genetics can learn to use it (see Table 3 below for a list of resources for brushing up on genetics). Below are instructions, tips, and advice on how to get started using this resource.

What can I use PharmGKB for?

PharmGKB has a wide variety of information on drugs, including their chemistry, how they interact with different biological pathways to produce a desired medical effect, and how this effect may be changed by specific gene mutations. Studying how mutations in a person's genes can make a drug more or less effective is part of a medical field called pharmacogenomics. This information might be of interest to you if you, or someone you know, have been prescribed a medication, or if you are curious about drug availability and effectiveness for different medical conditions. You can explore many resources on the PharmGKB website. Here we will walk through using this knowledge base to look up a drug of interest and learn how mutations in certain genes can cause people to have different responses to a drug. You can find additional resources and tutorials for learning more about using PharmGKB at the end of this tutorial.

How can I look up a drug and find out more information on it?

Here we will show you how to look up a drug to learn more about it. For the purpose of simplifying the directions, we will use the drug clopidogrel as the example in this tutorial.
  1. Go the PharmGKB website, http://www.pharmgkb.org, shown in Figure 1 below. (Note: This link will open a new window so you may more easily follow the steps.)
  2. To see all of the drugs on the website with genetic information, under "PGx Research" on the bottom right click on "Drugs with genetic information," circled in red in Figure 1 below.
    1. Alternatively, to go directly to information on your drug, you can type your drug name into the search box circled in green in Figure 1 below. If you do this, from the results page select your drug (such as "Drug: clopidogrel [pgx research]") and then skip to step 5 below.
PharmGKB Pharmacogenomics Knowledge Base has information on different drugs, including their chemistry, pathways they are involved in, and how they are affected by genetics., Medical Biotechnology BioMed science project
Figure 1. PharmGKB has information on drugs, drug interactions in the body, and how genetic variants affect these interactions. To see the drugs on the website with genetic information, click on "Drugs with genetic information," circled in red above. To go directly to information on your drug, search for your drug name in the search box circled in green above.
  1. The resulting page, shown in Figure 2 below, will alphabetically list drugs for which there is genetic information available. For our clopidogrel example, click on the letter "C" at the top, circled in yellow in Figure 2 below.
You can browse PharmGKB to find a number of drugs that have genetic data available in the database., Medical Biotechnology BioMed science project
Figure 2. PharmGKB has genetic information on a large number of drugs, which you can browse on this page. Drugs are listed alphabetically; for example, to find clopidogrel, click on the letter "C," circled in yellow above. Symbols to the left of the drug name indicate what kind of genetic information is available on that drug.
  1. Scroll down until you see "Clopidogrel" and click on it.
  2. The drug page, shown in Figure 3 below, contains a large amount of information on a given drug.
When you look up a drug on the PharmGKB you will find a large amount of information, from the chemistry of the drug, signaling pathways it is involved in, and genetics related to varied responses to the drug., 
Medical Biotechnology BioMed science project
Figure 3. PharmGKB provides a large amount of information for a given drug. This tutorial helps you to explore tabs titled "Clinical PGx," circled in yellow above, "PGx Research," circled in green above, "Pathways," circled in red above, and "Is Related To," circled in light blue above.

Some drugs may have more information available than others, and not all of the tabs shown in Figure 3 above may be present. Table 1 below gives an overview of the different types of information generally provided for each tab. Explore the tabs to learn more about the drug.

Tab Name What Information It Provides
Clinical PGx
  • Clinical information on alleles (versions) of genes that the drug is known to interact with (pharmacogenomics information). This includes effectiveness, dosing, and available genetic tests.
PGx Research
  • List of alleles associated with drugs, with a different allele on each row.
  • The rsID for the allele, listed under "Variant (build 132)." You can click each rsID to find more information on it.
  • The drug(s) the allele is known to interact with, listed under "Drugs."
  • The DNA mutation for the allele, listed under "Alleles."
  • The type of mutation in the allele, such as whether it is a missense mutation or a mutation in a stop codon, listed under "Function."
  • The amino acid mutation for the allele, listed under "Amino Acid Translation."
Overview
  • General information on the drug, including its names, chemical structure, and medical uses.
Properties
  • Description of how the drug functions on a molecular level, including how it interacts with its target molecules.
Pathways
  • Links to graphical representations of signaling pathways (human biochemical pathways) that the drug is involved in, along with textual descriptions of the pathway(s) and pharmacogenomic drug function.
Is Related To
  • Genes that are related to the action of this drug. Genes from the "Clinical PGx" tab may also be listed here.
  • Related drugs or drugs known to interact with the drug in the body when taken together.
  • Diseases treated by the drug or diseases that may be caused as a side effect of taking the drug.
Downloads/LinkOuts
  • Links to additional information on the drug on other websites.
Table 1. This table shows what information each PharmGKB tab provides for a drug. Not all tabs may be present for a given drug.

I want to look up a drug and find out why it has different effects when taken by different people. How can I do this?

Pharmacogenomics can help explain why people have different reactions (both side effects and/or degrees of positive response) to a drug. That is, the specific alleles (versions) of a gene (or genes) that a person has inherited changes their personal biology in a way that makes a drug more or less effective. You can use the PharmGKB database to learn about the pharmacogenomics of individual drugs.

Once you have completed the tutorial section "How can I look up a drug and find out more information on it?", the next step you can take is to find genetic alleles that cause a person to have a different response to a drug than other people. There are several places on the PharmGKB to obtain genetic information for a given drug. Here we will explore the primary locations for this information: sections located in the "Pathways," "Clinical PGx," and "Is Related To" tabs. For the purpose of simplifying the directions, we will use the drug clopidogrel as the example in this tutorial.

  1. Once you have located the PharmGKB page for your drug of interest (step 5 above), click on the "Pathways" tab, circled in red in Figure 3 above.
  2. On this page, you can find links to different signaling pathways (biochemical pathways) that the drug is involved in.
    1. Click on "Clopidogrel Pathway, Pharmacokinetics."
  3. This page has a graphical representation of the signaling pathways that the drug is involved in, followed by a description of how the drug is metabolized (broken down in the body) and interacts with other members in the pathways.
    1. For example, you can locate clopidogrel and P2RY12 (a protein that functions as a receptor on the outside of platelets) in the image. Then, you can read the text following the image to learn how exactly clopidogrel interacts with P2RY12.
    2. Clicking on any protein name in the image will take you to a page on it, as shown in Figure 6, and to be discussed, below.
    3. In the textual "Description," various scientific papers are referenced in brackets, for example "[Article: 11127873]."
    4. Specific gene alleles associated with unusual responses to using this drug may also appear near the end of the text, sometimes by their allele rsID. Alleles are alternative forms of a gene that occur through mutation of the DNA. Alleles can be either newly created or passed along from parent to child for many generations, and they may be good or bad.
      1. The rsID, the letters "rs" followed by a short string of numbers, identifies a specific allele in other databases. See step 9 below for details.
  4. To find a list of different genes and their alleles that are associated with a patient having an unusual reaction to the drug, click on the "Clinical PGx" tab, circled in yellow in Figure 3 above.
  5. In the "Clinical PGx" tab, click on the "Clinical Annotations" tab, and there for each allele you can find the following information, as shown in Figure 4 below:
    1. The heading for each clinical annotation includes the rsID for the allele that that annotation discusses. The rsID is how an allele can be identified in databases.
      1. For example, an allele listed for clopidogrel is rs12248560.
    2. The heading for each clinical annotation also includes the name of the gene.
      1. For example, the allele above is a version of the CYP2C19 gene.
    3. The boxes on the right (next to "CC," "CT," "TT," or a different amino acid pair) describe how scientific studies found the allele to be related to the drug.
      1. You will need to register an account with PharmGKB to access the information in these boxes. It can take up to 72 hours to create an account, so plan ahead.
    4. Under "Level of Evidence" is a number that represents how strong the evidence is that supports the information listed in the boxes on the right for this allele.
    5. Under "Diseases" is a list of diseases associated with this allele.
    6. Below this table of alleles, you can click on the link titled "Download a summary of all Clinical Annotations available" to download a document that contains this same kind of clinical information for all drugs and related alleles in the PharmGKB database.
PharmGKB pharmacogenomics drug clinical annotations multiple·gene·alleles image
Figure 4. Multiple gene alleles may be associated with patients having an unusual response to a drug. These alleles, along with identifying information and a description of how they are associated with the drug, are listed in the "Clinical PGx" tab, circled in yellow in Figure 3 above, in the "Clinical Annotations" tab shown in this figure.
  1. You can find additional information on the genetics associated with your drug of interest by clicking on the "Is Related To" tab, circled in light blue in Figure 3 above.
  2. In the "Is Related To" tab, click on the "Related Genes and Targets" tab, shown in Figure 5 below. This tab has a list of links to different proteins that the drug interacts with. Gene names from the "Clinical Annotations" tab in the "Clinical PGx" tab may appear here.
    1. Click on "CYP2C19," circled in green in Figure 5 below.
On PharmGKB, for a given drug in the 'Related Genes' tab, you will find a concise list of genes that are associated with the drug.  Clicking on a gene name will take you to more information about it., 
Medical Biotechnology BioMed science project
Figure 5. Several genes may be associated with patients having an unusual response to a drug. You can find a concise list of these genes, with links to more information on the genes, in the "Is Related To" tab, which is circled in light blue in Figure 3 above, by clicking on the "Related Genes and Targets" tab. This tutorial uses gene CYP2C19, circled in green above, as an example.
  1. This page, shown in Figure 6 below, contains a large amount of information on a given protein and the gene that encodes for it. It is similar to the main drug page shown in Figure 3 above.
On PharmGKB, a large amount of information is available on a given gene associated with a drug.  From any drug page, you can navigate to its associated gene information by going to the 'Related Genes' tab and clicking on a gene name., 
Medical Biotechnology BioMed science project
Figure 6. PharmGKB usually provides a large amount of information on any given protein, similar to the pages for drugs. The information available in the tabs is similar to the tabs for drugs, explained in Table 1 above.

Some genes may have more information available than others, and not all of the tabs shown in Figure 6 above may be present. The tabs given here are similar to the ones for drugs shown above in Table 1 above, except that the ones here are for proteins and their genetics. Table 2 below gives an overview of the different types of information generally provided for each tab that was not already covered in Table 1 above.

Tab Name What Information It Provides
VIP
  • Detailed description of the protein, including its normal function, how it interacts with other molecules and drugs, specific allele variants, key scientific publications, and more.
Haplotypes
  • List of alleles for a given gene, with a different allele on each column listed by its rsID. You can click each rsID to find more information on the allele, or you can search for it in the SNP database, which is discussed below in step 9.
  • The haplotype, or combination of alleles that are statistically likely to be inherited together, is also displayed. You can click each haplotype to find more information on it and the related alleles.
Table 2. This table shows what information will be provided in tabs on the PharmGKB page for a protein and its genetics. Information for tabs not listed here will be similar to what is listed in Table 1. Not all tabs may be present for a given protein.
  1. You can find more information on a given gene allele by going to the Gene SNP database. To see how to do this, go to the NCBI Gene & SNP Tutorial.
    1. In the tutorial under the section titled "How can I look up a gene and find out more information on it?", you can search for your gene of interest.
      1. In the tutorial under the following section titled, "I want to look up a gene involved in a genetic disease and find out how it is mutated in that disease. How can I do this?", you can look at the different alleles for this gene and search for your specific allele.
      2. To search directly for your allele in the database using its rsID, go to step 3 in the NCBI Gene & SNP tutorial, which discusses the SNP database.

I do not understand some of the terms or concepts used in the PharmGKB Pharmacogenomics Knowledge Base. Where can I look up more information?

Resource Area Resource Name Website What You Will Learn
General Genetics Genetics Home Reference
(National Institutes of Health)
http://ghr.nlm.nih.gov/ Terms and concepts related to genetics and what genes cause different genetic conditions.
Human Genetics and Medical Research: A Revolution in Progress
(National Institutes of Health)
http://history.nih.gov/exhibits/
genetics/index.htm
General genetics concepts, including what genes are, information on the Humane Genome Project, and how gene therapy works. Includes a cartoon guide for kids.
Human Genome Project Information
(Oak Ridge National Laboratory)
http://www.ornl.gov/sci/
techresources/
Human_Genome/
project/info.shtml
How the Human Genome Project was done and what it can tell us about our genetics.
Learn.Genetics, Genetic Science Learning Center
(The University of Utah)
http://learn.genetics.utah.edu/ Terms and concepts related to genetics, including how DNA turns into protein and heredity. Includes an animated "tour" and a game to build a DNA molecule.
DNA from the Beginning
(Cold Spring Harbor Laboratory)
http://www.dnaftb.org/ Terms and concepts related to general genetics and information on historic genetics experiments.
Gene Screen app
(Cold Spring Harbor Laboratory: Dolan DNA Learning Center, Harlem DNA Lab & DNA Learning Center West)
http://www.dnalc.org/
resources/
gene_screen_app.html
Interactive explanations of general genetics concepts, including inheritance. Interactive iPhone/iPod Touch app.
Genetics & Diseases Genes and Disease
(National Center for Biotechnology Information)
http://www.ncbi.nlm.nih.gov/
books/NBK22183/
Genes and the genetic disorders and diseases that they cause.
Your Genes, Your Health
(Cold Spring Harbor Laboratory: Dolan DNA Learning Center)
http://www.ygyh.org/ Information on genetic diseases, including their incidence, testing, symptoms, causes, treatments, and more.
Gene Testing Understanding Cancer: Gene Testing
(National Cancer Institute at the National Institutes of Health)
http://www.cancer.gov/
cancertopics/
understandingcancer/
genetesting/
What genes are and how to have gene testing done.
Table 3. There are many resources available online to help provide a basic understanding of genetics concepts and terms.