Genetics of differential drug response Drugs & Genetics: Why Do Some People

Genetics of differential drug response

Drugs & Genetics: Why Do Some People Respond to Drugs Differently than Others?

PART 1 For a drug basic info on gene changes in humans

PART 2 Later in semester look up mutations in NCBI database

Abstract

In a survey conducted from 2007 to 2010, the U.S. Centers for Disease Control and Prevention reported that about 49% of people in the United States had taken at least one prescription drug during the past month, and about 22% of people had taken three or more prescription drugs. People are prescribed drugs all the time, but prescriptions can be dangerous because people can have different responses to drugs. These responses largely have to do with genetic mutations.

Why are some genetic mutations associated with a different response to a drug? In this science project, you will explore an online drug and genetics database to identify how a genetic mutation can be associated with how a person’s body processes, and responds to, a certain drug.

Objective

Determine why some gene mutations cause people to respond differently to a drug

First, go to the PharmGKB Pharmacogenomics Knowledge Base Tutorial and follow the steps through the section titled “How can I look up a drug and find out more information on it?”.

On step 4 of the tutorial section, for clopidogrel and other drugs that you investigate, browse through the information in the “Overview,” “PGx Prescribing Info,” and “Drug Labels” tab.

What does the entry on clopidogrel tell you about its medical use? What kind of patients would use clopidogrel? How does the drug function, in general?

For each drug that you investigate, record in table below the following information:

The generic and trade (brand) names of the drug.

What kind of chemical the drug is, and what other drugs it is related to. You may want to draw its chemical structure.

What medical condition the drug is used to treat.

The drug’s general effect on the body.

In the “Overview” tab you should also find information about how the drug functions on a molecular level.

Continue through the PharmGKB tutorial, following the steps through the section titled “I want to look up a drug and find out why it has different side effects when taken by different people, based on their genetics. How can I do this?”

For clopidogrel (prevents heart attacks or strokes) and other drugs that you investigate, when looking at the “Pathways” tab (steps 1 to 3 in the tutorial) look at the graphical representation of the pathway, and read the description of the pathway below the image, paying special attention to descriptions of the different components shown in the image and how they interact with the drug. In the “Overview” tab for clopidogrel there should be a section that discusses the pharmacogenomics of the drug, which is how the 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.

Alleles are alternative forms of a gene that occur through mutation of the DNA. In the case of clopidrogel you would want to think about and answer these questions:

How does clopidogrel interact with P2RY12? What is P2RY12?

What do CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4/5 all have in common?

What drug-drug interactions is clopidogrel involved in?

Read about how patients’ responses to clopidogrel are variable, paying special attention to the proteins that make the response variable.

How does ABCB1 interact with clopidogrel?

If it is discussed for your drug of interest, record the gene name and rsID for gene alleles that are associated with variable response to the drug.

Fill out Table 2 with this information and add additional rows as needed. Table 2 will be discussed in further detail.

For example, for clopidogrel an allele of the ABCB1 gene with the rsID of rs1045642 can affect absorption of the drug in patients with cardiovascular diseases. For clopidogrel there are other genes and variants discussed as well.

If there are multiple links to pathways listed in the “Pathways” tab, look at all of them.

Continue through the tutorial by looking at the “Clinical Annotations” tab (steps 4 to 5), and read over the different alleles that are associated with the pharmacogenomics of clopidogrel and other drugs that you investigate.

Continue filling out Table 2 in your notebook as you collect more information on your selected alleles.

Look for alleles of genes that were discussed in the “Overview” tab in the pharmacogenomics section. There may be a lot of alleles listed, and they may not all be of genes that were covered in the “Overview” tab.

For example, for clopidogrel in the “Clinical Annotations” tab you will find an allele of the CYP2C19 gene. The rsID rs4244285 will be there, and the information listed for this allele should be similar or related to its description you read in the “Overview” tab.

If the “Overview” tab did not give information on alleles and rsIDs for a drug that you are investigating, when looking at each allele listed in the “Clinical Annotations” tab, pay special attention to the gene name (under “Gene”), the allele’s rsID (under “Variant”), the effect of the interaction with the drug (under “Type”), and the phenotypic impact of the variant (under “Phenotype”).

Look at the “Pathways” tab again and locate the allele’s gene name. How does the protein that this gene encodes interact with the drug in the pathway?

How do you think the change in the allele affects how the body responds to the drug?

To find additional information on the gene alleles that are associated with a varied response to the drug, continue through the tutorial by exploring the information available in the “Related To” tab (steps 6 to 8).

Identifying the Mutations

Once you have the information on a drug of interest and the proteins it interacts with in the body, you can figure out why a simple mutation in the DNA that encodes for this protein is associated with a different response to the drug. WILL DO THIS PART NEXT TIME

You should have already copied and started filling out Table 2 in your notebook. Table 2 has been partly filled in with information on alleles of some genes, specifically ABCB1, P2RY12, and CYP2C19, that are associated with a varied response to the drug clopidogrel. In this part of the science project, you will fill in the rest of Table 2 and add additional rows with information on other drugs and alleles.

Generic Name of the Drug

Protein that has Variable Response to the Drug

How this Protein Interacts with the Drug

rsID of an Identified Allele

Exon, Intron, or Other?

Codon Sequence Change (DNA)

Codon Sequence Change (mRNA)

Amino Acid Sequence Change

Effect

Clopidogrel

ABCB1

Involved in the intestinal absorption

rs1045642

Exon

ATT → ATA

AUU → AUA

I [Ile] → I [Ile]

 

Clopidogrel

P2RY12

 

rs2046934

Intron

N/A

N/A

N/A

 

Clopidogrel

CYP2C19

 

rs4244285

Exon

ATG → GTG

AUG → GUG

M [Met] → V [Val]

Changes from a neutral, nonpolar amino acid to another neutral, nonpolar amino acid.

Table 2 for you to fill out.  Fill in the information in the empty cells and add additional rows with information on other drugs and alleles.

Generic Name of the Drug

Protein that has Variable Response to the Drug

How this Protein Interacts with the Drug

rsID of an Identified Allele

Exon, Intron, or Other?

Codon Sequence Change (DNA)

Codon Sequence Change (mRNA)

Amino Acid Sequence Change

Effect

Will continue later analyzing the effect of human population mutations on drug effects in semester after practicing the NCBI database

DO ON YOUR OWN ONE OF THE DRUGS LISTED BELOW THE SAME WAY YOU DID IN EXAMPLE

Generic Name

Trade Name

Major Use

Atorvastatin

Lipitor

Lowers cholesterol

Azathioprine

Imuran

Treats rheumatoid arthritis

Capecitabine

Xeloda

Treats breast and colorectal cancers

Carbamazepine

Tegretol

Treats seizures

Celecoxib

Celebrex

Treats arthritis

Clopidogrel

Plavix

Prevents blood clots

Erlotinib

Tarceva

Treats lung, pancreatic, and other cancers

Fluorouracil

Efudex

Treats many types of cancers

Gefitinib

Iressa

Treats lung cancer and other cancers

Imatinib

Gleevec

Treats many types of cancers

Irinotecan

Camptosar

Treats colorectal cancer

Mercaptopurine

Purinethol

Treats leukemia

Tamoxifen

Nolvadex

Treats and prevents breast cancer

Thioguanine

Tabloid

Treats leukemia

Warfarin

Coumadin

Prevents blood clots