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 may be of interest if you, or someone you know, has been prescribed a medication or if you are just curious about what drugs are available for different medical conditions and how they work. 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. Aternatively, 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.

3. 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.

4. Scroll down until you see "Clopidogrel" and click on it.
5. The drug page, shown in Figure 3 below, contains a large amount of information on a given drug.

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.

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.

6. 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.
7. 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.

8. 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.

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.

9. 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?

• For a general discussion of the concepts used in PharmGKB, from the main PharmGKB page (http://www.pharmgkb.org), click "Help" on the top of the page. Scroll down to "Questions about the data/knowledge in PharmGKB" or "Questions about Pharmacogenomics." Under one of these headings, click on the link that is most relevant to what you want to find out.
• To learn more about biology/genetics in general, see Table 3 below.

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